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Method Development for Laser Diffraction
 

Method Development for Laser Diffraction

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Generating reliable, accurate particle size data is dependent upon the quality of the method. This presentation shows how HORIBA develops methods for laser diffraction particle size analyzers. This ...

Generating reliable, accurate particle size data is dependent upon the quality of the method. This presentation shows how HORIBA develops methods for laser diffraction particle size analyzers. This information will be useful for any laser diffraction analyzer and specifically the LA-950 Particle Size Analyzer.

Ian Treviranus, from HORIBA Scientific, covers the following topics:

Overview of sampling & dispersions
Effect of ultrasound & air pressure
Case studies
Making life easy with the Method Expert
ISO recommendations

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  • The LA-950 can accurately detect particles as small as the 40 nm latex shown on the left, and the 30 nm Ludox silica on the right. <br /> The Ludox is the sample we use to verfiy performance of the DT-1200 system. <br /> It is well characterized and accepted as being 30 nm in size. <br /> The LA-950 has the best small particle detection performance of any laser diffraction particle size analyzer. <br /> The Mastersizer 2000 for example can not measure anything below 70 nm. <br />
  • Precision is the ability of the instrument to get the same answer for the same material in repeat tests. The data shown was 24 samplings on one instrument. The data shows the precision of both sampling and instrument. Repeat measurements of the same sample in the instrument would characterize the precision of this one instrument. <br />
  • Resolution is the ability of the instrument to measure small differences in particle sizes. Resolution is difficult to specify, because it can have many possible meanings. In the case of the user, it would be most important to test a series of samples that track the variables of interest used to characterize the performance of the instrument for that specific use. <br />
  • Perhaps the most important measure of resolution is how small a difference in the sample itself will generate a difference in the measurement. These changes may come from additional processing (milling or agglomeration) or to differentiate between different batches of material. <br /> Polystyrene Latex (PSL) NIST traceable standards are the easiest standards to use, but are significantly different from a vast majority of the materials manufactured and used in industry. This example does show the ability of the instrument to differentiate between a 553nm and a 600nm material. <br />
  • This is an example of a mixture of three distinctly different size materials. Can the instrument identify that there are distinct distributions within the total sample? If so, are the relative amounts of the different components reported properly? <br /> Some companies have focused on tests to show closely spaced polystyrene latex as individual peaks in the overall distribution. As this example shows, it is possible, but the user must decide if this is a valid test of the ability of the instrument to respond to their samples. <br />
  • This is another example of a mixture of three distinctly different size materials, but at a much larger size range. Instrument response can vary over the measurement range. Experiments should be designed to characterize performance in the range of the final application. <br />
  • Resolution can also be the ability of the instrument to determine small amounts of a material outside of the main range of the sample, whether larger or smaller. A small amount of fines or coarse material can be a very important indicator of process problems. The ability to respond to these small amounts of material before they become a large contributor to the total particle distribution is a very important feature. <br />

Method Development for Laser Diffraction Method Development for Laser Diffraction Presentation Transcript

  • Method Development Ian Treviranus ian.treviranus@horiba.com www.horiba.com/us/particle © 2013 HORIBA, Ltd. All rights reserved.
  • What we’ll talk about  Accuracy, precision, resolution  Setting goals, ISO/USP input  Wet method development  Dry method development  Q&A © 2013 HORIBA, Ltd. All rights reserved.
  • Starting point  Instrument is fully functional  Suitable sample for technology Counters are classic example  Stay current with free webinars Particle size essentials, method development, sampling & dispersion advice, DLS and zeta potential technology reviews © 2013 HORIBA, Ltd. All rights reserved.
  • General concerns  Data correlation (larger topic, def. doable!)  Reliable results (accuracy? precision?)  Generating real results  Validating methods  Effect of ultrasound/air pressure on results  Dispersing powders (webinar TR005, TR016)  Validating data (webinar TR004) © 2013 HORIBA, Ltd. All rights reserved.
  • Featured technologies  LA-950 Laser Diffraction  SZ-100 Dynamic Light Scattering & Zeta Potential  CAMSIZER & CAMSIZER XT Dynamic Image Analysis  PSA300 Static Image Analysis  SA-9600 Flowing Gas BET Surface Area © 2013 HORIBA, Ltd. All rights reserved.
  • LA-950: Laser Diffraction  Particle size performance leader  Ninth generation  Ultra durable  Lowest total cost of ownership  Suspension, emulsion, powder, paste, gel  10 nanometer – 3 mm © 2013 HORIBA, Ltd. All rights reserved.
  • Dynamic Range 0.01 – 3000 µm  Widest wet measurement range  Only system to measure 30 nm! 30 nm silica © 2013 HORIBA, Ltd. All rights reserved. 40 nm latex
  • Section Overview     Goal: Reproducible method that tracks product performance Choose measurement approach (dry vs. suspension) Lock down RI Vary measurement settings that can influence result  Dry: measurement duration, concentration, air pressure  Wet: sampler selection, dispersion, duration, concentration, energy (mixing + ultrasound)  Test method (reproducibility)  Meet ISO, USP or internal guidelines  Check COV at d10, d50, d90 © 2013 HORIBA, Ltd. All rights reserved.
  • Goals for any Method  Reproducible method that tracks product performance  You might have other goals  Accuracy: tricky subject, is it the “real” particle size?  Repeatability: liquid suspension re-circulating in sampler  Reproducibility: prepare, measure, empty, repeat  Resolution: optimize to find second populations  Match historic data (sieves), but quicker, easier technique  Use structured approach for any decision/choice that may influence result  Have data to support selections made  Document process so colleagues understand your choices © 2013 HORIBA, Ltd. All rights reserved.
  • Accuracy vs. Precision LOW ACCURACY LOW PRECISION LOW ACCURACY HIGH PRECISION HIGH ACCURACY LOW PRECISION HIGH ACCURACY HIGH PRECISION (A) Low accuracy, low precision measurements form a diffuse, off-center cluster; (B) Low accuracy, high precision measurements form a tight off-center cluster; (C) High accuracy, low precision measurements form a cluster that is evenly distributed but distant from the center of the target; (D) High Accuracy, high precision measurements are clustered in the center of the target. © 2013 HORIBA, Ltd. All rights reserved.
  • Accuracy  Is it the “real particle size”?  Comparison to referee technique  Microscope (image analysis) is referee technique for particle characterization  Two kinds of image analysis: Dynamic image analysis; particles flowing Static image analysis; particles sit on slide on automated stage © 2013 HORIBA, Ltd. All rights reserved.
  • Image Analysis to Verify Dynamic: particles flow past camera © 2013 HORIBA, Ltd. All rights reserved. Static: particles fixed on slide, stage moves slide
  • Proposed Guidelines Scheme for outlining particle evaluation for preclinical studies. Decision tree outlining particle evaluation for Phase I clinical studies © 2013 HORIBA, Ltd. All rights reserved.
  • Proposed Guidelines Scheme for outlining particle evaluation for Phase III clinical studies © 2013 HORIBA, Ltd. All rights reserved.
  • Types of Precision  Repeatability Prepare sample, add to wet sampler, recirculate, measure same multiple times (suspensions only) Provides limited information  Reproducibility Prepare sample, measure, drain, repeat (suspensions + dry) Distinguishes great methods © 2013 HORIBA, Ltd. All rights reserved.
  • Repeatability 24 Sam plings of Polyst yr ene Lat ex 30 25 Fr equency % 20 15 10 5 0. 19 7 0. 25 8 0. 33 9 0. 44 5 0. 58 3 0. 76 5 1. 00 4 1. 31 8 1. 72 9 2. 26 8 2. 97 6 3. 90 4 5. 12 2 6. 71 9 8. 81 5 -5 0. 15 0. 11 4 0 Size ( micr ons) © 2013 HORIBA, Ltd. All rights reserved.
  • Reproducibility  Reproducibility: prepare, measure, empty, repeat  What would be good reproducibility? Look at accepted standards Measure 3 times, calculated COV at d10, d50, d90 – COV (RSD) = st dev/mean * 100 ISO13320 – COV < 3% at median d50 – COV < 5% at d10 & d 90 USP<429> – COV < 10% at median d 50 – COV < 15% at d10 & d 90 © 2013 HORIBA, Ltd. All rights reserved. Note: double all limits When d10, d50, or d90 < 10 µm
  • Resolution  Ability to measure small differences in particle size  Small differences between successive samples (different production lots) are most important  Detection limit of small amount of material outside of main size distribution  Best defined by user’s real-world requirements © 2013 HORIBA, Ltd. All rights reserved.
  • Is this High or Low Resolution?  Resolve size difference between two materials of similar size  552nm and 600nm PSL  Measured separately: high resolution  Measure together: low resolution, would blend peaks  Laser diffraction is a “resolution limited” technique © 2013 HORIBA, Ltd. All rights reserved.
  • Resolution: Multi-modal 83nm, 204nm, 503nm PSL Resolution of multiple modes in a single sample Next peak 2x of previous size © 2013 HORIBA, Ltd. All rights reserved.
  • Resolution: Multi-modal 100µm, 200µm, 400µm glass beads Next peak 2x of previous size Resolution is independent of where you are on size scale © 2013 HORIBA, Ltd. All rights reserved.
  • Resolution: Outlier Populations  0.1 micron silica material  2% by weight of ~1 micron quartz standard added  Original slide showed .25% © 2013 HORIBA, Ltd. All rights reserved.
  • Resolution: Outlier Example Median Size : 0.031 μm Median (Peak 1) : 0.031 μm Median (Peak 2) : 1.75 μm 0.05wt% Median Size : 1.65 μm Top left: LUDOXTM-50 PSD, Lower left: 0.1wt% Geltech 1.5 PSD Top right: 0.05wt% Geltech 1.5 in LUDOX Result shows both oversize particle detection & very good accuracy for both components. *See AN179 CMP SLURRY MEASUREMENT USING LASER DIFFRACTION © 2013 HORIBA, Ltd. All rights reserved.
  • Wet Method Development © 2013 HORIBA, Ltd. All rights reserved.
  • Wet Method Workflow  First determine RI  Choose solvent (water, surfactants, hexane, etc.)  Sampler selection: sample volume  Pump & stirrer settings  Concentration  Measurement duration  Does the sample need ultrasound? Document size-time plot Disperse sample, but don’t break particles Check for reproducibility © 2013 HORIBA, Ltd. All rights reserved.
  • Determine Refractive Index  Real component via literature or web search, Becke line, etc.  Measure sample, vary imaginary component to see if/how results change  Recalculate using different imaginary components, choose value that minimizes R parameter error calculation © 2013 HORIBA, Ltd. All rights reserved.
  • LA-950 Method Expert © 2013 HORIBA, Ltd. All rights reserved.
  • Sampler Selection  Larger, broad distributions require larger sample volume  Lower volume samplers for precious materials or solvents LA-950 Sample Handlers Dispersing Volume (mL) Aqua/SolvoFlow 180 - 330 MiniFlow 35 - 50 Fraction Cell 15 Small Volume Fraction Cell 10 Note: FractionCell has only magnetic stir bar, not for large or heavy particles Median (D50): 114 µm Sample Amount: 1.29 mg Bio polymer © 2013 HORIBA, Ltd. All rights reserved. Median (D50): 35 nm Sample Amount: 132 mg Colloidal silica Median (D50): 9.33 µm Sample Amount: 0.165 mg Magnesium stearate
  • Pump & Stirrer  Must be high enough to suspend & circulate heavy particles  Not so high that bubbles are introduced  Adding energy – can disperse loose agglomerates  Measure at several settings & select optimum  Can be automated in software (see right) © 2013 HORIBA, Ltd. All rights reserved. Exp # Agitation Circulation Dmean (nm) D10 (nm) D90 (nm) 1 1 1 187.03 137.5 245.7 2 1 3 184.23 135.9 242.1 3 3 1 187.28 137.8 245.8 4 3 3 184.61 136.1 242.5 5 1 1 185.32 136.3 243.7 6 1 3 184.04 135.8 241.8 7 3 1 184.13 135.8 241.9 8 3 3 184.98 136.4 242.9 Parameters Selected: Agitation: 2 Circulation: 2
  • Concentration  High enough for good S/N ratio  Low enough to avoid multiple scattering  Typically 95 – 80 %T  Measure at different T%, look at Chi Square calculation d50 Chi2 © 2013 HORIBA, Ltd. All rights reserved.
  • Measurement Duration  Long enough for reproducibility  Typically 5 sec, up to several minutes  Longer time for large, broad distributions  Can be automated in software  Could be used for robustness testing during method validation © 2013 HORIBA, Ltd. All rights reserved.
  • Ultrasonic Dispersion  Adding energy to break up agglomerates – disperse to primary particles, without breaking particles  Similar to changing air pressure on dry powder feeder  Typically set to 100% energy, vary time (sec) on  Investigate tails of distribution  High end to see if agglomerates removed  Small end to see if new, smaller particles appear (breakage)  Test reproducibility, consider robustness  Note:  Do not use on emulsions  Can cause thermal mixing trouble w/solvents - wait  Use external probe if t> 2-5 minutes © 2013 HORIBA, Ltd. All rights reserved.
  • LA-950 Method Expert  Level (power)  Time on  Iterations  Delay  Generate result graphs © 2013 HORIBA, Ltd. All rights reserved.
  • Wet Method Development Case Study Microcrystalline Cellulose © 2013 HORIBA, Ltd. All rights reserved.
  • Effect of Ultrasound: MCC © 2013 HORIBA, Ltd. All rights reserved.
  • Effect of Ultrasound: MCC 180 0 sec 160 140 15 sec µ m ) 120 ( ez S i D90 D50 D10 5 sec 10 sec 100 40 sec 20 sec 80 60 sec 60 40 20 0 1 2 3 4 5 6 7 Ultrasound (sec) © 2013 HORIBA, Ltd. All rights reserved. 8 9 10 11 12 13
  • Reproducibility Test at 15 sec  ISO13320  USP<429> – COV < 3% at median d50 – COV < 10% at median d 50 – COV < 5% at d10 & d 90 – COV < 15% at d10 & d 90 © 2013 HORIBA, Ltd. All rights reserved.
  • Precision Test Automation From LA-950 Software © 2013 HORIBA, Ltd. All rights reserved.
  • Reproducibility  58 methods  Image analysis for morphology  Laser diffraction for PSD  If RSD for d50 < 20%, then acceptable for QC environment  Note: RSD increases with decreasing size Not acceptable per USP<429> Acceptable *Barber, Keuter, and Kravig, A Logical Stepwise Approach to Laser Diffraction Particle Size Distribution Analysis Methods Development and Validation Pharmaceutical Development and Technology, 3(2), 153-161 (1998) © 2013 HORIBA, Ltd. All rights reserved.
  • Sampler Selection Remove points from not acceptable region using Fraction Cell Not acceptable Acceptable *Barber, Keuter, and Kravig, A Logical Stepwise Approach to Laser Diffraction Particle Size Distribution Analysis Methods Development and Validation Pharmaceutical Development and Technology, 3(2), 153-161 (1998) © 2013 HORIBA, Ltd. All rights reserved.
  • Dry Method Development © 2013 HORIBA, Ltd. All rights reserved.
  • Dry Method Workflow  First get sampling right & determine RI  Measure at 3 different pressures (low, medium, high)  Determine optimum pressure based on good dispersion while not breaking particles  Can also compare dry vs. wet measurements  Adjust other settings to optimize sample concentration & duration  Ideally measure all of powder placed into the sampler  Segregation can occur on vibrating tray  Constant mass flow rate important for stable concentration during measurement  Once settings chosen, test reproducibility © 2013 HORIBA, Ltd. All rights reserved.
  • Dispersion vs. Breakage Theoretical Actual ez S i ez S i Stability Increasing energy Increasing energy Higher air pressure or longer ultrasound duration © 2013 HORIBA, Ltd. All rights reserved.
  • Dispersion vs. Breakage  Dispersion and milling can be parallel rather than sequential processes Theoretical Actual © 2013 HORIBA, Ltd. All rights reserved.
  • Pressure Titration 2 bar 1 bar 3 bar © 2013 HORIBA, Ltd. All rights reserved.
  • Dry Method Development Case Studies Magnesium Stearate Microcrystalline Cellulose © 2013 HORIBA, Ltd. All rights reserved.
  • Effect of Air Pressure: Mg Stearate High = 3 bar Mid = 2 bar Low = 1 bar © 2013 HORIBA, Ltd. All rights reserved.
  • Effect of Air Pressure: Mg Stearate 18 16 14 12 D90 10 D50 8 D10 6 4 2 0 1 2 3 D90 15.258 14.394 12.822 D50 8.626 8.149 7.502 D10 4.862 4.564 4.234 © 2013 HORIBA, Ltd. All rights reserved.
  • Reproducibility Test at 3 Bar © 2013 HORIBA, Ltd. All rights reserved.
  • Reproducibility Test at 2 Bar © 2013 HORIBA, Ltd. All rights reserved.
  • Reproducibility Test at 1 Bar © 2013 HORIBA, Ltd. All rights reserved.
  • Effect of Air Pressure: MCC © 2013 HORIBA, Ltd. All rights reserved.
  • Effect of Air Pressure: MCC 200 150 D90 100 D50 D10 50 0 1 2 3 D90 161.158 160.713 144.259 D50 65.938 64.599 58.578 D10 25.76 24.308 22.655 © 2013 HORIBA, Ltd. All rights reserved.
  • Reproducibility Test at 3 Bar © 2013 HORIBA, Ltd. All rights reserved.
  • Wet and Dry Comparison © 2013 HORIBA, Ltd. All rights reserved.
  • Summary  Must have representative sample  Powders: select air pressure  Suspensions: wet, disperse  Check accuracy w/microscope  Investigate system settings: concentration, agitation, ultrasound  Design for maximum precision  Follow guidelines in standards © 2013 HORIBA, Ltd. All rights reserved.
  • Thank you ありがとうございました ขอบคุณ ครับ 谢谢 Gracias ‫اشك ر‬ ْ‫كُ ر‬ Grazie धनयवाद Σας ευχαριστούμε Tacka dig Danke 감사합니다 © 2013 HORIBA, Ltd. All rights reserved. Merci Большое спасибо நனற Obrigado
  • www.horiba.com/particle Ian Treviranus Product Line Manager ian.treviranus@horiba.com Talk to us, ask questions labinfo@horiba.com Receive news of updates View application & technical notes (170+), webinars (70+), white papers. © 2013 HORIBA, Ltd. All rights reserved.