Transcript Advantages

Review of Alternative Particle Sizing Techniques to the ACI for MDIs
Sarah D’Oyley – 3M Health Care Ltd, Loughborough
Louisa Nelmes, Chris Blatchford – 3M Health Care Ltd, Loughborough (contact authors)
Introduction
• Time consuming and laborious
• Particle bounce due to electrostatic charging of
particles by the plastic actuator
• Adhesion of particles to the walls of the impactor due
to van der Waal’s forces
• Insufficient options for automation
• Cut-off diameters vary with flow rate
• Reduced flow rate due to high air flow resistance in
the large volume impactor
Disadvantages
The size of particles delivered by Metered Dose Inhalers (MDIs) depends on the
following factors:• The pressure inside the canister
• The physical/chemical properties of the propellant and other excipients
• The active, it’s concentration and the delivered volume
• The metering valve and delivery outlet design
• The mouthpiece and cleanliness of the spray orifice
The size of the particles is critical since it affects not only the dose quantity and the
delivery site (only particles <5µm reach lower regions of the lung), but also the clinical
efficacy and tolerability.
Currently, MDI particle size information submitted to the Regulatory authorities is
usually based on Andersen Cascade Impactor (ACI) data. This is the most widely used
compendial method for particle size analysis since it is fully validated and is based on
direct chemical assay of the active. However, the methods are laborious and time
consuming. This poster describes and compares alternative methods for MDI particle
size analysis.
Non-Real Time Particle Sizing Methods
Laser Diffractometer
A laser beam is used to produce a parallel beam of coherent, monochromatic light
through which the aerosol passes. A Fourier transform lens then focuses the diffraction
pattern generated by the particles in the aerosol onto a photodetector consisting of a
series of concentric ring-diodes. The detector measures the radial distribution of
diffracted light intensity and then relates this to a size distribution.
Advantages
• Determines particle size distribution by mass (not no.)
• Not susceptible to coincidence problems
• Operates over a wide range between 0.5-200 µm
• Fast/highly reliable technique with automated recording
• Can estimate MMAD from median diffraction diameters
Disadvantages
• If aerosol is too far from the lens, it can cause
‘vignetting’ where the light scattered is not captured
• Lack of combination product & active/surfactant
discrimination
• At high drug concentrations, particle-particle scattering
can lead to beam obscuration and biased results
• A differing refractive index between air and propellant
can cause beam steering
Marple-Miller Impactor
This works on the same principle as the ACI with the main difference being that the
aerosol is collected in cups instead of plates, thus minimizing errors caused by
inter-stage wall deposition. As with the ACI, there is the disadvantage of analysis time
being labour intensive. Several different models are on the market.
Next Generation Impactor (NGI)
Unlike the ACI, the NGI has been specifically developed for use in the
pharmaceutical industry. New instruments are built to strict specifications
that are known to conform to published calibration data. It is a 7-stage
impactor with cut off diameters ranging between 0.23-11µm. Airflow is
horizontal instead of vertical as with the ACI.
Advantages
• Removable cups thus reducing analysis time
• Operates at wide range of flow rates (30-100 l/min)
Disadvantages
• As for ACI, with exception of ‘time consuming’
• Can undersize particles of some formulations, likely to be due
to particle bounce and/or incomplete evaporation of volatile
constituents.
Liquid Impingers
Real Time Particle Sizing Methods
Malvern
Spraytec
Experimental
Comparison of the APS and the Malvern Spraytec
Applies the Mie scattering theory to data, which takes into account the combined effects
of diffraction, refraction and absorption.
Advantages
• Offers the best general solution for particles <50µm
Disadvantages
• Measurement errors can occur due to beam steering and
presence of irregular shaped particles
• Lack of combination product & active/surfactant
discrimination
Phase-Doppler Analysis
This uses the Doppler effect to obtain information about particle size/velocity. Scattered
light is detected as individual particles cross through a series of interference fringes
formed from intersecting laser beams.
Twin, Metal & Multi-Stage Impinger
Twin: the dose collected in the throat and 1st flask makes up the non-respirable fraction
(particles >6.4µm) whilst the remaining dose is collected in the 2nd flask (particles
<6.4µm) of the glass apparatus.
Metal: a single stage is used at a 60 l/min flow rate. Particles >9.8µm are collected on a
sintered glass disc, with finer particles collected on a back up filter.
Multi-Stage: based on 4 stages with cut-off diameters = 15.3, 6.4 & 2.8µm. A glass
filter retains particles <2.8µm. Size separation occurs based on differences in aerosol
velocity & separation distance between the entry tube and impaction plate.
Advantages
Disadvantages
• Liquid collection media, hence no issue with particle
bounce and re-entrainment
• Easy/quick to use – only 2 stages (Twin & Metal only)
• Multi-Stage gives wider range of data
• Two stages do not give in-depth particle size
distribution (Twin & Metal only)
• Operates at a constant flow rate of 60 l/min
• Multi-Stage is time consuming
Aerosizer
Determines particle size by timing flight of individual particles along a known distance
between 2 laser beams. Operates effectively in range 0.3-15µm aerodynamic diameter
and is capable of highly consistent results based on Mass Median Aerodynamic Diameter
(MMAD) for different formulations that are within  5 % of the mean. However, on
direct comparison with the ACI, the Aerosizer appears to underestimate MMAD values
Advantages
Disadvantages
Advantages
Andersen Mark II Cascade Impactor
Enabling your success
• Data is number-weighted rather than mass-weighted
• Particle sphericity is assumed in the analysis
• Fraction of particles provide signals that meet criteria
Results and Discussion
• Lack of combination product & active/surfactant
discrimination
Disadvantages
Advantages
• Can be applied in line with a patient,
• It is simple, robust and fast (30 doses per hour)
Disadvantages
• Number-weighted rather than mass, assumes particles are
spherical, and there is potential for sample loss at the inlet
• Lack of combination product & active/surfactant
discrimination
• Size distribution pattern based on several thousand
particles can be obtained in less than 20 seconds
Electronic Low Pressure Impactor (ELPI)
• Susceptible to overloading due to particle coincidence
in the measurement zone at high aerosol concentrations,
leaving particles undetected
• Does not possess ability to discriminate between
active drug and excipients/surfactant, and also between
actives within a combination product
Advantages
• Can give real time measurements therefore quick
• Automatic data recording, which measures temporal
rather than spatial aerodynamic diameter
Disadvantages
• Lack of combination product & active/surfactant
discrimination
• Small particles can cause erroneous signals on the higher
stages leading to skewing of MMAD values
This is a single particle detector that constructs size distribution patterns from time-offlight measurements of particles as they accelerate across 2 laser beams.
• Multi-stage thus giving wide range of data
• Fully validated direct chemical assay method
Disadvantages
Uses the macroscopic principles of optical absorption & scattering to generate pictures
of the aerosol cloud.
Aerodynamic Particle Sizer (APS)
Advantages
• Can measure wide dynamic size range of 0.3-10 µm
Light Obscuration
Cascade Impactors
Current models of the ACI are made from stainless steel and the set up
includes an induction port (throat), 8 single stage impactors and a filter.
Particles >10 µm are collected in the throat. The dose collected on and below
stage 3 is considered as the respirable fraction.
Advantages
• Able to add vertical extensions to throat to give more
time for the volatile constituents to evaporate
• Capable of making measurements within short time
• Operates efficiently in the range 0.3-15 µm
• <1% of the aerosol is drawn into the APS
• Lack of combination product and active/surfactant
discrimination
• Loss of sensitivity at limit of detection of ~ 0.5µm
Uses voltage changes across impactor plates to calculate particle size distribution.
Summary / Conclusion
The closest alternative technique to the ACI is probably the NGI, with reduced analysis
times, however it does depend on formulation type it is used for.
For rapid analysis of particle size, two of the best alternatives to ACI are probably the
APS and Spraytec. The accuracy of the Spraytec is likely to be higher than the APS,
since the whole of the aerosol plume is sampled as opposed to 0.1% of it. Ultimately,
both instruments rely on the assumption that all particles are spherical. Furthermore,
all real-time sizing methods have the disadvantage of being unable to
discriminate between other active or excipient materials present.
Ultimately, it depends on what the PS technique is being used for as to which
PS technique is best suited.
3 Drug Delivery Systems