Laser diffraction particle size analyzer (PSD)

1. Method Development and
Validation : Laser Scattering
Particle Size Distribution (PSD)
Analyzer
Md. Saddam Nawaz

2. FDA guidance: when should particle size be
measured?
International Conference on Harmonization;
Guidance on Q6A Specifications:
Test Procedures and Acceptance Criteria for New Drug
Substances and New Drug Products: Chemical Substances*
3.3.1 New Drug Substances
(b) Particle size: For some new drug substances intended for use in solid
or suspension drug products, particle size can have a significant effect on
dissolution rates, bioavailability, and/or stability. In such instances, testing
for particle size distribution should be carried out using an appropriate
procedure, and acceptance criteria should be provided.
Decision Tree #3 provides additional guidance on when particle size
testing should be considered.

3. FDA guidance: when should particle size be
measured?

4. Method Development
Goal: Reproducible method that tracks product
performance
Choose measurement approach (dry vs. wet)
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

5. Goals
Reproducible method that tracks product
performance
Use structured approach for any decision/choice that
may influence result
Have data to support selections made
Document process so others (in future) understand
the decisions

6. Method development: available guidance
for laser diffraction measurements
ISO13320-1: Section 6.4
 Dv50 - 5 different readings: COV < 3%
 Dv10 and Dv90: COV < 5%
 “Below 10μm, these maximum values should be doubled.”
USP <429>
 Provides reproducibility ranges
 Dv50 or any central value: <10%
 Dv10, Dv90 or any non-central value: <15%
 “Below 10μm, these maximum values should be doubled.”
EP 2.9.31 provides similar advice to USP<429>

7. Method development: Sub-Sampling

8. Sampling from Drums

9. Technique: Grab Sampling
PLACE SPATULA INTO POWDER
EXTRACT SMALL AMOUNT FOR ANALYSIS
ACCEPTABLE FOR NARROW DISTRIBUTIONS
SEGREGATE LARGE AND SMALL WHEN POLYDISPERSE
LARGE PARTICLES PERCOLATE UPWARD
SMALL PARTICLES GRAVITATE DOWNWARD
EASY METHOD
MOST USED METHOD

10. Grab Sampling from Bottle
When a powder is stored in a container,
it can be mixed by rolling and tumbling
the container. The container should not
be more than half to two-thirds full. It is
important to perform this action before
“grabbing” a sample with a spatula.
Then pull sample with a spatula…..

11. Technique: Coning & Quartering

12. Technique: Chute Riffling

13. Technique: Rotary Riffling
The best method of representative splitting of powders
is the ROTARY RIFFLER.

14. Lab Sample Dividers

15. Sampling Technique Error Levels

16. Method development: Wet Method

17. Choosing the Solvent (Dispersent)
When powders are dispersed in liquid the
solvent must meet the following criteria:
Negligible reactivity with powder
Does not swell or shrink particles
 Have refractive index (RI) different than the sample
 Be free from bubbles & particles
 Have suitable viscosity to enable recirculation
 Be compatible with materials in the analyzer

18. Choosing the Solvent (Dispersant)

19. Dispersion Definitions

20. How to check for wetting
If the particles float on top and do not penetrate the water surface,
they are not wetted. This is usually a bad sign.
If the particles break through surface and sink, they are a) wetted or
b) so big that gravity is more important than surface tension. If it is
case you are in luck!

21. If the going gets tough…

22. If the going gets tough…
Try a series of options.
Here I make a series of suspensions and check them
by eye, then measure.

23. Common Surfactants
Igepal CA630 Ethoxylated octyl phenol
Nonionic
Triton X100 Octylphenoxypolyethoxy
ethanol Nonionic
Tween 20 Polyoxyethylene sorbitan
Nonionic
Aerosol-OT Dioctyl ester Na Sulfo
succinic acid Anionic

24. Sodium Hexametaphosphate
(NaPO3)6

25. Sodium Hexametaphosphate
(NaPO3)6
Increasing Sodium Hexametaphosphate Concentration

26. Refractive Index
Refractive Index is defined by two components – REAL and
IMAGINARY
RI = n + ik
Where:
n = the real component, which is the ratio of the velocity of
light in a vacuum to the velocity of light in the material =
c/vp
c = speed of light in vacuum
Vp = speed of light in particle (liquid, air)
k = the extinction coefficient of the material
i = √ - 1

27. Determine RI
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

28. RI: Imaginary Component
For transparent particles use 0 for the
imaginary component
For slightly opaque materials use 0.01
or 0.1
For opaque materials use 1.0 or higher
Values can exceed 1.0 (see below*)

29. RI Choosing for Mixtures

30. Determine RI experimentally

31. Concentration

32. Detection limit and Range
Assessment of the detection limit of the laser
diffraction technique is not required as part of
method validation.
The range of the instrument should ideally
cover the size range of the sample. For
modern laser diffraction instrumentation with
size ranges between 20nm and 2000μm this
normally presents no problem for most
pharmaceutical samples.

33. Specificity
Specificity, in terms of whether or not the technique
is appropriate to the material under analysis, should
be addressed as part of method development and
does not have to be revisited for method validation.
Laser diffraction provides a good method for
assessing small changes in the size distribution in this
regard. However, it is difficult to differentiate
between the different components within
pharmaceutical dosage forms using the technique.

34. Robustness
Measurement Duration
b) Repeatability / Sample
Measurement Stability

35. Measurement Duration
The purpose of this exercise is to determine a suitable
measurement duration, which will then be used for the
repeatability, reproducibility and intermediate precision
exercises.
A cycle of ten measurements should be performed for durations
of 2, 5, 7, 10 and 15 seconds.
For particles with a median size (D(v,0.5)) of >10 micron the
Relative Standard Deviation (RSD) should be <3%
For particles with a median size <10 micron the RSD must be
<6%. This reflects the Fact that smaller particles are more
difficult to disperse.

36. Measurement Duration
Variation of lactose D(v,0.5) with measurement duration.

37. Repeatability /
Sample Measurement Stability
In order to determine whether samples are stable over the
period of analysis and not subject to agglomeration, de-
agglomeration or dissolution, it is necessary to monitor the
particle size distribution at known time points.
Measurements could be taken after 1, 3, 5, 7 and 10 minutes.
At least five repeat measurements should be obtained at each
time point.
For material that has a D(v,0.5) greater than 10 microns an
acceptable time point is defined when the following conditions
are met: D(v,0.5) RSD <3%, D(v,0.1) and D(v,0.9) RSD <5%.
For material that has a D(v,0.5) less than 10 microns an
acceptable time point is defined when the following conditions
are met: D(v,0.5) RSD <6%, D(v,0.1) and D(v,0.9) RSD <10%
(ISO13320).

38. Repeatability /
Sample Measurement Stability
Variation of lactose size over time
(mean of 5 repeat measurements are shown)

39. Air Pressure (Dry measurement) /
Ultrasound (wet measurement)
A suitable pressure is one at which dispersion of the particles is
achieved but milling of the particles is not occurring.
Often both dispersion and milling occur simultaneously (which
leads to a broadening of the distribution)
By measuring the same amount of sample (ideally sampled to
single shot size by a spinning riffler) at different pressures, the
pressure at which maximum dispersion is achieved without
milling can be ascertained.
The use of ultrasound in wet measurements is very similar. ISO
13320 recommends that ultrasound can be used to assist
dispersion. Too much ultrasound can fracture friable
pharmaceutical particles, although this is extremely unusual.
Ideally measurements should be taken before, during and after
ultrasound to examine what effect sonication has on the
robustness of the measurement.

40. Effect of Ultrasound
(wet measurement)

41. Pump and Stir Rates
The pump and stir speeds used during
a measurement should be examined as
part of method development. The
chosen conditions should be capable of
suspending all the material without
causing air entrainment (a particular
problem if surfactants are being used).

42. Pump and Stir Rates
Effect of varying the stirrer rate on the result obtained for a typical lactose.

43. Linearity / Obscuration
It is suggested
that
obscurations of
5, 10, 15,
20 and 25% are
investigated in
the same way
that the
measurement
duration test
was
performed, with
the acceptable
RSDs being
similarly
specified.

44. Reproducibility
Variation in the results obtained for seven separate scooped sampled lactose samples.

45. Reproducibility

46. Intermediate Precision
(REPRODUCIBILITY by 2nd Analyst)
Lactose results obtained for a second analyst.

47. Method Development: Dry Method

48. Method Development: Dry
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

49. FDA Recommendations
The FDA’s guidance regarding the validation of
particle size analysis methods states that the
validation concepts associated with other analytical
methodologies, such as HPLC, do not transfer to
techniques such as laser diffraction. Instead, analysts
are only required to assess the intermediate precision
and robustness in order to show that the selected
method provides a reproducible method of controlling
product quality

50. Conclusions
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

51. “Quality cannot be tested into
products; i.e., quality should be
built in by design”- ICH
THANK YOU FOR YOUR
ATTENTION!

52. Q and A