Exploration of a novel PAT for wet granulation

Transcription

1 Drag Force Flow Sensor as a Tool for Real-Time Assessment of Granule Densification in High Shear Wet Granulation: Effect of Process Parameters and Application to Scale-up in Placebo and Brivanib Alaninate Formulations Exploration of a novel PAT for wet granulation Involved: Ajit S. Narang Tim Stevens Brian Breza Kevin Macias Divyakant Desai Sherif Badawy Dilbir Bindra Valery A. Sheverev Vadim P. Stepaniuk IFPAC January 26 th, 215 1

2 Scope Presenting results of dynamic measurements of flow forces in a high-shear wet granulator using Lenterra s Drag Flow Force (DFF) Sensor Series One Placebo formulation 3 Liter PharmaConnect Granulator 3 tests with different concentrations of binder (HPC) 1%,3%, and 5% particle size distribution (PSD) of granules measured in parallel using focused beam reflectance measurement (FBRM) C35 probe Series Two high drug load (62% w/w) Brivanib Alaninate Two DFF probes used simultaneously in two locations within granulator 3 tests in PharmaConnect 1L with 48%, 58% and 67% w/w water added 1 test on PharmaConnect 6L with 58% water added 2

3 Sensing technology Measurement direction Granulator lid Sensor holder Probe: thin (1-4 mm) hollow cylindrical pin inserted into flow streamline geometry - minimal intrusion does not trap solid components of the flow so the sensor is not paralyzeable easy installation with no gap between sensor and wall/holder Detection principle: two optical strain gages Fiber Bragg Gratings (FBG) affixed diametrically opposite on the inner surface the FBG assembly detects a minute deflection of the tip of the pin (< 1 nm) and which is related to equivalent force on the tip in addition to force, the FBG assembly measures temperature directional measurement measures force projection on the plane formed by FBGs Pillar 3

4 Measurement system Probe with insulated fiber-optic cable as long as needed Opto-electronic Interrogator/controller compact rugged measurement rate up to 5 Hz (1 khz) Host computer Connected to interrogator via USB Measurement software Post-processing software Technology advantages: Tolerant to chemically aggressive /explosive flows; chemically and electrically passive only outside surface of the hollow pillar is exposed to the flow no electronics within the length of the cable FBGs consume zero power therefore probe is intrinsically safe and can be used in most explosive environments Miniature size/non intrusive No moving parts apart from minute deflection of the pin Local measurement in two dimensions perpendicular to the probe axis High measurement rate 5 Hz in tests reported - 1 khz achievable 4

5 What does it measure in granulator? Force Force Force Time Time Time Fast response: impacts of lumps granules of 1-3 mm size provide distinct pulses of force The force magnitude due to interaction of a single particle is proportional to the particle mass: indicator of density F = 2 π 6 fvρd 3 f v is mechanical frequency of the probe pin is granule velocity 5

6 What does it measure in granulator?-2 In fluids - drag force (combination of normal and shear forces) Impacts of numerous small granules provide continuous signal π 2 F Aρv A is the cross-section of the collision 16 Some information retrievable from the continuous signal: Binder content Density of small IN AVERAGE granules Information from the lump granule impacts: Distribution of pulse amplitudes should correlate with granule size distribution Mass of the granule can be calculated from the pulse amplitude and duration 6

7 Typical measurement cycle Water added Granulator on Granulator off Series Two (Brivanib) Test 4: 58% water in 6L granulator Measurement points Upper plot: 1,25, Bottom plot: 1 Detail (zero subtracted) Sine fit Period of the sine fit matches time between blades passing the probe Model: continuous periodic signal (sine fit) overlapped with random peaks of various amplitudes 7

8 Measurements Series One: Formulation and Objective Placebo Formulation Microcrystalline cellulose 57% Lactose monohydrate 37.5% Croscarmellose sodium Hydroxypropyl cellulose (HPC) Granulated with 4% w/w water Total of 2kg of water added over 18 s Batches Test 1- HPC 1% Test 2- HPC 2% Test 3- HPC 5% Objective: Compare responses of C35 and DFF probes for different binder levels Focused beam reflectance measurement (FBRM) C35 probe for in-line measurement of chord length distribution (CLD) DFF sensor for high speed flow force measurement 8

9 Series One: Sensor placement DFF Sensor C35 Probe DFF Sensor Granulator: PharmaConnect 3L Impeller tip speed: 4.8 m/s Blade RPM: 21 Chopper RPM: 1 Sensor tip position: 1 above the blade ~3/4 relative radius ¼ rotation downstream the chopper 9

10 Series One: DFF Sensor Raw signal with zero correction Water added Test 1: 1% HPC batch Test 2: 3% HPC batch Impeller starts Impeller stops Test 3: 5% HPC batch Common for three batches: Steep increase in the signal during water addition and wet massing Decrease in the signal soon after water addition stops Saturation after ~7 s Differences: Signal magnitude is noticeably different between batches increasing with HPC content 1

11 Series One: Post processing Data Test 1: 1% HPC batch Test 2: 3% HPC batch Test 3: 5% HPC batch Peak magnitude (average over 1 blade rotations) Sine fit amplitude (average over 1 blade rotations) Peak magnitude, N Time, s Sine fit amplitude, N Time, s High resolution data collection allows processing options such as FFT DFF sensor is able to differentiate batches made with different HPC % w/w content as well as different stages of processing 11

12 Series One: DFF Sensor Peak distribution statistics Test 1: 1% HPC batch Test 2: 3% HPC batch Test 3: 5% HPC batch Distributions over 1 blade occurrences (9.47s) Bin size.2 N Peak magnitude distribution characterizes dispersion of granule masses 12

13 Series One: Sieve analysis Particle size distribution.45.4 Normalized Amount Particle Size (Microns) % HPC 1% HPC 5% HPC Certain correlation to the DFF sensor data can be found analyzing the amounts for large granules (>1.5 mm) However, no significant difference in the overall particle size distributions, especially between the 1% HPC and 3% HPC batches (cr. slide 1, sine amplitudes) DFF sensor may quantitate a binder-level in-process attribute that is not necessarily PSD dependent 13

14 Test 1: 1% HPC batch Square Weighted (Mass) Time (minutes) 5 y 1 1 Chord Length (um) 1 Chord Length Distribution by FBRM Square Weighted (Mass) Test 2: 3% HPC batch y Test 3: 5% HPC batch 8 y 15 Time (minutes) Chord Length (um) 1 Square Weighted (Mass) Time (minutes) Chord Length (um) 1 No significant difference in CLD between the batches (e.g. 3% and 5% HPC) This does not correlate with DFF sensor data Assuming CLD provides granule size and DFF sensor granule mass, combined measurements may give information about granule density distribution 14

15 Series One: Basic results The peak magnitudes, sine-fit amplitudes, distribution widths were a function of the concentration of HPC used in the batch The DFF sensor was able to capture anticipated differences in wet mass consistency with different concentrations of binder Basic statistical analysis of peak magnitudes suggested potential for the development of a procedure to quantitatively characterize such parameters of the wet mass as densification, and particle growth 15

16 Series Two: Formulation and Objective Total of four tests with the same formulation composition: Two sensors were installed to explore if the dynamic signal is location dependent Brivanib Alaninate 62% w/w Microcrystalline cellulose 29% w/w Croscarmellose Sodium 4% w/w HPC EXF 5% w/w Granulator size and water content: Test #1: 1L granulator 48% w/w Test #2: 1L granulator 58% w/w Test #3: 1L granulator 67% w/w 58% w/w is in the center of process design space Tests #1,2,3 were aimed to explore if DFF sensor data may generate a quality and/or measurand that would separate the 58% batch from both 48% batch and 67% batch Test #4 was aimed to see if such a quality/measurand is scaleindependent Test #4: 6L granulator 58% w/w 16

17 Series Two: Sensor placement Granulator: PharmaConnect Top Sensor r t h Side Sensor t r s h s Blade velocity at probe tip 1L granulator 6L granulator Top sensor 2.59 m/s 2.35 m/s Side sensor 3.59 m/s 4.1 m/s Top sensor 1L granulator 6L granulator r, cm h, cm r, cm h, cm 8.2 (54%) (49%) 2.5 Side sensor 11.1 (74%) (85%)

18 Series Two: Tests 1,2, 3, 4 raw data zero adjusted Typical end of granulation Test 1: 1L-67% water Side sensor Top sensor Test 3: 1L-48% water Test 2: 1L-58% water Test 4: 6L-58% water Similar signals from either sensor in each test 67% and 48% resemble those for placebo formulation 58% is VERY DFFERENT 18

19 Comparison 1L and 6L granulators Top Sensor/time Side Sensor/time Top Sensor/blade no. Side B2 Side Sensor/blade Sensor no. 19

20 Peak magnitude (average over 1 blade rotations) A:Top Sensor B: Side Sensor Peak magnitude, N Peak magnitude, N A1 Typical end of granulation , Time, s 1,5 2, 5 1, Time, s 1,5 2, 1 1 A2.8 Peak magnitude, N Peak magnitude, N.6.2 B B2.6 Test 2 Test Test 1: 67% Water 1 liter granulator 1 15 Blade number 2 25 Test 2: 58% Water 1 liter granulator Blade number Test 3: 48% Water 1 liter granulator 2 25 Test 4: 58% Water 2 6 liter granulator

21 Sine fit amplitude, N Sine Fit Amplitude (average over 1 blades) A:Top Sensor Typical end of granulation A1 Test 1 Test 2 Test 3 Test 4 Sine fit amplitude, N B: Side Sensor B1 Test 1 Test 2 Test 3 Test 4 Sine fit amplitude, N Time, s Test 1: 67% Water 1 liter granulator A Blade number Test 2: 58% Water 1 liter granulator Sine fit amplitude, N Time, s Blade number Test 3: 48% Water 1 liter granulator B2 Test 2 Test 4 Test 4: 58% Water 6 liter granulator21

22 Delay time, s Water %w/w Side sensor, 6L Top sensor, 6L Side sensor, 1L Top sensor, 1L Test 1: 67% Water 1 liter granulator Test 2: 58% Water 1 liter granulator Test 3: 48% Water 1 liter granulator Test 4: 58% Water 6 liter granulator 22

23 τf ; f Scale-independent measure: Delay time normalized by blade rotation time and effective granulation length is blade frequency 3 τ V ; V is granulation volume Dimensionless Top Sensor Side Sensor s/m Top sensor Side sensor Granulator volume, liters Granulator volume, liters Test 2: 58% Water 1 liter granulator Test 4: 58% Water 6 liter granulator 23

24 A novel in-line PAT (DFF sensor) Conclusions measures force by wet mass in a high shear granulator at high data acquisition rate provided a signal that was able to explain wet mass consistency and granule densification, distinct from granule PSD Measurements using a placebo and an active formulation: DFF sensor is readily capable of differentiating batches with different formulation composition (HPC% w/w content) process parameters (% w/w water used for granulation) different stages of processing DFF sensor time-to-peak response identifies a stage after the end of water addition when granulation processes reach maximum wet mass consistency DFF sensor can be used as a tool to identify the end point of a WG process with respect to granule densification or wet mass consistency, a parameter to enable robust formulation and process design efficient scale-up of WG processes Overall, flow force measurement using a cylindrical probe appears to be a promising technology for real-time monitoring and control of HSWG 24

25 Real-Time Assessment of Granule Densification in High Shear Wet Granulation and Application to Scale-up of a Placebo and a Brivanib Alaninate Formulation Journal of Pharmaceutical Sciences Ajit S. Narang, Valery A. Sheverev, Vadim Stepaniuk, Sherif Badawy, Tim Stevens, Kevin Macias, Avi Wolf, Preetanshu Pandey, Dilbir Bindra and Sailesh Varia Article first published online : 2 DEC 214, DOI: 1.12/jps Questions? 25