LABRAM Characterization Studies

Transcription

1 LABRAM Characterization Studies Juan Osorio Fernando Muzzio Department of Chemical and Biochemical Engineering Rutgers University 10/11/2005 1

2 Outline Mixing principles and mechanisms. Quantification of macro and micro mixing performance Case studies done at Rutgers Studies and Comparison with double-cone blender MgSt studies distribution Fractional Factorial Design Modeling (ongoing preliminary results) Evolution of mixedness as a function of time Velocity Profiles Particle Trajectory 2

3 Mixing Principles and Mechanisms - Quantification of Macro and Micro Mixing Performance 10/11/2005 3

4 Mixing principles and mechanisms - Quantification of macro and micro mixing performance 4

5 RAM and Double Cone Comparison 10/11/2005 5

6 Double Cone Blender Comparison 6

7 Operating Conditions LABRAM Double Cone 7

8 Results Comparison of cases with lowest RSDs from the LabRAM and double cone LABRAM shows better and faster mixing at the specific parameters 8

9 Temperature Profiles in RAM Mixing RAM mixing caused a temperature rise in the powder. Certain mixing parameters resulted in higher temperature increases as shown. Temperature seems to increase the most when more powder is present at higher acceleration. There was no significant temperature rise in the powder blended with the double-cone apparatus. 9

10 MgSt Distribution Studies in Tablets from Blends Produced in the RAM 10/11/

11 MgSt Distribution Studies Blend Avicel PH 200 (89.5%) + Chlorpheniramine (9%) + Cab-o-Sil (.5%) + MgSt (1%) 4 kg total Pre-Blending Procedure (V-blender) Chlorpheniramine is sieved in a 120 mesh before use Chlorphenirmaine and Avicel blended at 15rpm for 15 min Cab-o-Sil (M-5P) added and mixed for 25 rotations at 15 rpm MgSt added and and mixed for 25 rotations at 15 rpm Blender Procedure (Acoustic Mixer) 200g of original blend (100% fill level in the VOLUME vessel) mixed 100% intensity (62 Gs) in acoustic mixer for 1, 2, and 8 min Final blends used to make tablets in a Prester MgSt distribution in tablets studied using LIBS 11

12 Temperature Profile in RAM Mixing 12

13 Tablet Press Simulator- Prester Each Blend was tabletted using a Presster rotary press simulator system Kikisui Gemini 1545 Compression settings were determined for each blend to produce tablets with comparable mass Tablet mass: 400 ± 10 mg Tablets pressed at 10, 15 and 20 kn From 13

14 LIBS By ablating the tablet with lasers, samples occur at progressive depths Depth per shot dependent on several factors Allows for subsurface composition analysis From 14

15 Experimental Methods (LIBS) LIBS analysis was performed on 6 tablets from each blend 31 sites per tablet 5 shots per site 2Hz pulsed Nd:YAG laser w/ 1064 nm wavelength nm range 1200nm grating Chlorpheniramine represented by C2 peak at nm MgSt represented by Mg peak at nm C2 Peak Mg Peak 15

16 Results MgSt Distribution Studies 16

17 Results MgSt Distribution Studies 17

18 Experimental Characterization DOE Factor A B C D E Level API API Conc (%) Fille Level (%) t (min) Gs 0 micronized APAP Caffeine granulated APAP A fractional factorial design (1/9) is being used to determine the main effects Excipient: Avicel PH200 18

19 Results Mean API Concentration Concentrations are predicted using the NIR previously used for the LABRAM and double studies 19

20 Results Relative Standard Deviation RSD decreases with API concentration increasing and increasing acceleration Statistically significant factors contributing to the RSD (API content uniformity in the blend) are API concentration and acceleration For the materials and parameters used, the time of mixing is not significant, although higher acceleration results in better mixing 20

21 Results Mean Variance Mean Variance decreases with API concentration increasing and increasing acceleration Statistically significant factors to the mean variance (API content uniformity in the blend) are API concentration and increasing accelerations For the materials and parameters used, there is no significant difference for time of mixing 21

22 Results Temperature Temperature increases with fill level, time and acceleration. Statistically significant factors to the temperature changes are time of mixing and acceleration 22

23 RAM Simulations using Discrete Element Modeling (DEM) 10/11/

24 Modeling Parameters Mixing Parameters Acceleration (Gs) Amplitude (mm) f(hz) Simulation Parameters time step (s) = 10^ 5 25% Fill Level 320,000 Particles 50% Particle 1 50% Particle 2 Propety Beads Cylinder Poisson's Ratio Shear Modulus (Pa) 10^4 10^8 Density (kg/m³) Coeff. Of Restitution Coeff. Of Static Friction Coeff. Of Rolling Friction Radius (mm) Height (mm) 85 24

25 Modeling Simulation 25

26 Mixing Performance - Simulations The particles reached mixing at similar times (~15 seconds) The RSD is slightly lower for particles mixed at 90Gs 26

27 Particle Trajectory 27

28 Conclusions Comparison LABRAM and Double-Cone Comparison of cases with lowest RSDs from the LabRAM and double cone LABRAM shows better and faster mixing at the specific parameters RAM mixing caused a temperature rise in the powder. Certain mixing parameters resulted in higher temperature increases as shown. Temperature seems to increase the most when more powder is present at higher acceleration. There was no significant temperature rise in the powder blended with the double-cone apparatus. 28

29 Conclusions Characterization (Main Effects) DOE RSD decreases with API concentration increasing and increasing acceleration Statistically significant factors contributing to the RSD or Mean Variance (API content uniformity in the blend) are API concentration and increasing accelerations For the materials and parameters used, the time of mixing is not significant, although higher acceleration results in better mixing Temperature increases with fill level, time and acceleration Statistically significant factors to the temperature changes are time of mixing and acceleration 29

30 Conclusions DEM Simulations The particles reached mixing at similar times (~15 seconds) The RSD is slightly lower for particles mixed at 90Gs 30

31 Back-up and Informational Slides 10/11/

32 Operating conditions double cone and sampling method Shell RPM = 30 RPM Fill level : 25%, 65% Sampling method 18 samples/time point Sampling thief 32

33 Analysis method LABRAM and Double Cone Comparison NIR Spectroscopy Calibration curve Instrument: Thermo Antaris Analyzer Sample holder: Sample analyzed from the bottom of the vial Sample size = ~ 10 mg 33

34 FF DOE Fractional Factorial Design 27 Experiments Avicel PH200 Run API API Conc (%) Fille Level (%) t (min) Gs 1 micronized APAP micronized APAP micronized APAP micronized APAP micronized APAP micronized APAP micronized APAP micronized APAP micronized APAP caffeine caffeine caffeine caffeine caffeine caffeine caffeine caffeine caffeine granulated APAP granulated APAP granulated APAP granulated APAP granulated APAP granulated APAP granulated APAP granulated APAP granulated APAP

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