decoding the acronyms and finding insights...interpreting your psa results decoding the acronyms and...

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Interpreting Your PSA ResultsDecoding the Acronyms and Finding Insights

Ian [email protected]/us/particle


The Basics

Define Parameters

Choose Parameters

Interpret Results

Outline


The Workflow

+ +

=


The Problem

=


The BasicsParticle Particle Distribution


The BasicsParticle Size Particle Size Distribution

4 µm


The Basics

Which is the most meaningful size?

differentsize definitions

differentresults


The Basics

What sizes can be measured?


The Basics

Laser DiffractionEquivalent Spherical Diameter

Dynamic Light ScatteringHydrodynamic Radius

Image AnalysisLengths, Widths, Equivalent Spherical

Acoustic SpectroscopyEquivalent Spherical Diameter


The BasicsLaser DiffractionAssumes hard, spherical shape model

q% = amount of each sizeby volume


The BasicsDynamic Light ScatteringAssumes hard, spherical shape model

Frequency % = amount of each sizeby volume


The BasicsImage AnalysisMeasures particle projection no shape assumption

UndersizePassingQ3


The BasicsAcoustic SpectroscopyAssumes hard, spherical shape model


Quiz!


Understand the dataA little goes a long way!

Know something about the particles in your sample

Particles have multiple dimensions, know which dimension your analyzer measures!

Conclusions


Defining Parameters


Terms, Terms, and more Terms

Particle SizeMonomodal: One PeakBimodal: Two PeaksMultimodal: Multiple Peaks

Monodisperse: All particles have same sizePolydisperse: Particles have many sizes

Volume diameter: Diameter of a sphere having the same volume as the particle

Surface diameter: Diameter of a sphere having the same surface as the particle



Particle SizeFrequency% / q% / Amount of each size by volumep3 / Retained / Sph Vol%

Volume-based diameter Calculated from vol. distribution emphasizes coarse particles (larger volume)

Number-based diameter Calculated from number dist. (individual particles) emphasizes fine particles

Cumulative% on diameter % of distribution finer/coarser than specified size

Diameter on cumulative% Size at which a specified % of distribution is finer/coarser



Particle ShapeAcicular: Needle-shaped, rigidAngular: Edgy, hard anglesFibrous: Thread-like, non-rigidGranular/Blocky: Irregular-shaped, low aspect-ratioSpherical: Regular-shaped, unity aspect ratio

Aspect ratio: Breadth / length OR Length / breadthSphericity: How spherical is the particle?Roundness: How round is the particle?


Quiz!


Size Terminology

The most common designation is micrometers ormicrons. When very small, in colloid region, measured in nanometers, with electron microscopes or by dynamic light scattering.

10-10 10-810-9 10-610-7 10-410-5 10-210-3 10-1 10-0

meternanometer

Angstrom(Å)

micrometer millimeterMicron or µm mnm mm

0.1µm 1.0µm 10µm 100µm

100 nm


Visible Particles: Lint, Dust, width of the ridges of fingertips.

Human Hair

Proteins, Viruses, and Macro-Molecules

Emulsions and ColloidsSuspensions and fine powdersSuspensions and fine powdersDust and free flowing powders

Relative Size


Quiz!


Central Values

Mean Medianand Mode

Size

Freq

uenc

y

MeanWeighted AverageCenter of Gravity

Median50% Point

ModePeak of the distributionMost common value


Three spheres of diameters 1,2,3 units

What is the average size of these spheres?Average size = (1+2+3) ÷ 3 =2.00

This is called the D[1,0] - the number mean

12 3

What does “Mean” mean?


None of the answersare wrong they have just been calculated using different techniques

X Dnl = =+ +

=[ , ] .1 01 2 3

32 00

X Dns = =+ +

=[ , ] .2 01 4 9

3216

X Dnv = =+ +

=[ , ] .3 01 8 27

32 293

X Dsv = =+ ++ +

=[ , ] .3 21 8 271 2 3

2 57

X Dvm = =+ ++ +

=[ , ] .4 31 16 811 8 27

2 72

Many possible Mean values


D[4,3] which is often referred to as the Volume Mean Diameter [ VMD ]

D [4,D [4,3]3] ==∑∑

i i

i i

D nD n

4

3

Monitoring the D[4,3] value in your specification will emphasize the detection of large particles

Volume-based Mean diameter


Mode

Median

Mean

D[4,3]

Fre q

u enc

y

Size

Remember: D[4,3] is sensitive to large particles

Central Values revisited

MeanWeighted AverageCenter of Gravity

Median50% Point

ModePeak of the distributionMost common value


D(v,0.9)D(v,0.1)

Size µmD(4,3) sensitive to large particles

D(3,2)

D(v,0.5)median

D(v,1.0)Never use the D100!

sensitive to small particles

10% of the particles liebelow this diameter

90% of the particles liebelow this diameter

half are larger than this diameterhalf are smaller than this diameter

Most Common Statistics


Normal (Gaussian) Distribution Curveμ = distribution meanσ = standard deviationExp = base of natural logarithms

1σ 2σY = Exp [ - (x - μ)2

2σ2 ]

Standard Deviation

Mean

+1 STD DEV-1 STD DEV

+2 STD DEV-2 STD DEV

68.27%

95.45%


Polydispersity Index (PI, PDI)SpanGeometric Std. Dev.VarianceEtc…

Distribution Width


Quiz!


Be familiar with the nomenclature

Many parameters can describe distributionD50, D10, D90 commonly used

Which Mean do you mean?

Conclusions


Choosing Parameters


Choosing good statistics

Statistics describing the distribution must…Tell us about our processMust be relevantMust be controlled wellBe reproducible!

Poor precision is the result of either a poor method or poor statistical choices


Reproducibility!Prepare, measure, empty, repeat

What would be good reproducibility?Look at the accepted standards

ISO 13320COV < 3% at Median (D50) COV = 100 * (StDev / Mean)COV < 5% at D10 and D90

USP <429>COV < 10% at Median (D50)COV < 15% at D10 and D90

Note: All limits double when D50 < 10 µmNote: Must acquire at least 3 measurements from unique samplings

The Basis for Reliable Data


Unique, automatic feature in LA-950 software

Calculation Automation


At a distance of a few standard deviations, non-instrumental errors can dominate

Distribution Extremes


95% of the distribution is within 2 standard deviations from the Mean99.7% of the distribution is within 3 standard deviations from the mean

2 and 3 Standard Deviations


If we want the same level of reproducibility at the D99 value as the D50, we need to analyze similar amounts of material in the D99 histogram band

Reproducibility at the Extremes


Instead of specifying the D95, D99, D99.99, D100, DMax

Specify the % of material greater than a certain size

Better Method to Monitor Extremes


Quiz!


Parameters should reflect product performanceBut don’t make your life more difficult than it needs to be!

Look to appropriate standardsISO 13320, USP <429> can provide guidance

Avoid monitoring the extremes whenever possibleBetter to use D(4,3) when you want spec. to be sensitive to presence of large particles

Conclusions


Advanced Result Interpretation


GeneralMultiple ModesMultiple peaks can be better described individually

D50 D90D10


Laser DiffractionMultiple ScatteringWatch for finer “particles” appearing with increasing concentration


Multiple Scattering Example Zoom

0.00E+00

1.00E-01

2.00E-01

3.00E-01

4.00E-01

5.00E-01

6.00E-01

65 70 75

Detector Number (higher detector numbers for smaller particles)

Ligh

t Int

ensi

ty

1 Bottle2 Bottles3 Bottles4 Bottles5 Bottles6 Bottles7 Bottles8 Bottles9 Bottles10 Bottles

Multiple Scattering Example

0.00E+00

5.00E-01

1.00E+00

1.50E+00

2.00E+00

2.50E+00

45 50 55 60 65 70 75

Detector Number (higher detector numbers for smaller particles)

Ligh

t Int

ensi

ty

1 Bottle2 Bottles3 Bottles4 Bottles5 Bottles6 Bottles7 Bottles8 Bottles9 Bottles10 Bottles

Multiple Scattering


1 bar

2 bar

3 bar

Laser DiffractionDispersing AgglomeratesWatch for no change in coarsest particles with changing energy


High = 3 barMid = 2 barLow = 1 bar

Laser DiffractionBreaking ParticlesWatch for finer particles being created with increasing energy


Dynamic Light ScatteringRestricted DiffusionUse bulk viscosity for concentrated sampleApparent size shifts larger with increasing concentrationPolydispersity (distribution width) remains a constant


Dynamic Light Scattering

Dilute

Concentrated

Size

Inte

nsity

Multiple ScatteringIncident light scatters off of multiple particlesParticles appear smaller, distribution shifts finerDistribution broadens in comparison to dilute analysis


Dynamic Light Scattering

Aggregate

Size

Inte

nsity

Aggregation EquilibriumCannot remove aggregates when created by equilibriumFiltration will only remove already-formed aggregatesImportant test for understanding formulation stability


Electrostatic Effects

The electrostatic interaction of particlesOverlapping double layersgive larger size valuesSalt will suppress the double layer

Particles

Double Layer

Na+

Cl-Cl-

Na+

Na+

Cl-

Suppressed Double Layer


Image AnalysisOverlapping ParticlesCheck images of coarsest particles to verify


Image AnalysisNoise Detection as ParticlesCheck images of finest particles to verify


Image AnalysisInsufficient Particle CountVary number of particles detected/analyzed


Look at the distribution graphSee the forest AND the trees

Precision != AccuracyVary measurement and calculation parameters

Conclusions


For More Details

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