1. Sarah D’Oyley – 3M Health Care Ltd, Loughborough Louisa Nelmes, Chris Blatchford – 3M Health Care Ltd, Loughborough (contact authors) 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. Liquid Impingers 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 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 Disadvantages 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 Cascade Impactors Andersen Mark II Cascade Impactor 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 Multi-stage thus giving wide range of data Fully validated direct chemical assay method Introduction Non-Real Time Particle Sizing Methods Results and Discussion 3 Drug Delivery Systems Experimental Comparison of the APS and the Malvern Spraytec 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 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. Advantages Can measure wide dynamic size range of 0.3-10 µm Disadvantages Data is number-weighted rather than mass-weighted Particle sphericity is assumed in the analysis Fraction of particles provide signals that meet criteria Lack of combination product & active/surfactant discrimination Light Obscuration Uses the macroscopic principles of optical absorption & scattering to generate pictures of the aerosol cloud. 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 Electronic Low Pressure Impactor (ELPI) Uses voltage changes across impactor plates to calculate particle size distribution. 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 Review of Alternative Particle Sizing Techniques to the ACI for MDIs Enabling your success Real Time Particle Sizing Methods 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 Size distribution pattern based on several thousand particles can be obtained in less than 20 seconds Disadvantages 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 Aerodynamic Particle Sizer (APS) This is a single particle detector that constructs size distribution patterns from time-of- flight measurements of particles as they accelerate across 2 laser beams. 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 Disadvantages <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 Disadvantages 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 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. 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.