Rapid Screening Method For Aerosol Particle Size Distribution Biology Essay


The United States and European Pharmacopeia presently encourage the use of multi-stage cascade impactors such as the Andersen Cascade impactor (ACI) and the Next Generation Impactor (NGI); for the measurement of the aerosol aerodynamic- particle size distribution (APSD) in orally inhaled pharmaceuticals (OIP) such as nebulizers and dry powdered inhalers (DIP). These orally inhaled pharmaceuticals (OIP) are the key to 'ground-breaking' research into treatments of many respiratory related diseases. However, methods that employ multi-stage cascade impactors can be very slow and highly time, labour and cost intensive.

The concept of Abbreviated impactor measurements (AIM) is the promised future of APSD analysis. Abbreviated impactor based measurements allow for the determination of coarse particle fractions (CPF), particle fine fraction (FPF) and extra-fine particle fraction (EPF) respectively. These calculated data can be directly compared to those derived from measurements run with the multi-stage cascade impactors (CI) to establish the improvements of the abbreviated methods and validate reliability of results.

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This literature review focuses on an introduction to the idea of aerosol aerodynamic-particle size distribution (APSD) measurements and its importance to the pharmaceutical industry and community as a whole. It also introduces cascade impactors, their importance and some of the different types commercially available.

However, the main aim of this review is to give valuable insight into the presently researched advantages of an abbreviated impactor compared to a multi-stage cascade impactor. And ultimately introduce the future project which is aimed at 'The Development of a rapid screening method for aerosol particle size distribution (APSD) using the fast screening impactor (FSI) with the UV spectrophotometric detection' in industry.




An orally inhaled pharmaceutical (OIP) is a portable medical device, used for the delivery of pre-dosed drug compounds into the human body via the pulmonary drug delivery route. The major advantage of the pulmonary drug delivery route is that it directly targets the lungs through systemic therapy, making the mode of action of orally inhaled pharmaceuticals (OIP), very quick.[2]

There are different types of orally inhaled pharmaceuticals (OIP) include:

Metered dose inhalers (MDI) - Pressurized canister releases medication into the mouth through a mouthpiece once pressed down.

Nebulizers - Operates by converting liquid medication to aerosol droplets that can be inhaled. Can be available in respiratory cycle form, breath-enhanced form or solely breath-actuated form.[2]

Dry powdered inhalers (DPI) - Medication is available in dry powdered form and operates based on deep inhalation of the user.

Nasal Sprays - Technically not an orally inhaled but a nasal inhaled pharmaceutical as it is mainly used for the local administration of nasal decongestants, steroids or anti-histamines.

Orally inhaled pharmaceuticals (OIP) are mainly prescribed for the treatment of respiratory related diseases such as asthma and Chronic Obstructive Pulmonary Disease (COPD).[3] Some pressurized metered dosed inhalers can be sometimes used with an accessory called a spacer, to also ensure accurate drug delivery.

Figure 1: Showing some different types of orally inhaled pharmaceuticals (OIP)

(Image copyright MSP corporation. http://www.mspcorp.com/InhalerTesting.pdf[2])


Aerosols are very tiny solid particles or liquid droplets ranging from 0.01-100µm, suspended in air. Drug compounds must be released from inhaled pharmaceuticals in the form of an aerosol to allow for its transportation down to the lungs and into the blood stream.[3] The pulmonary drug delivery route made up of the nasal cavity, mouth, bronchi and alveoli; constitute a particle size gradient (i.e. an aerosol flow sieve) within the human body. The aerosol aerodynamic-particle size and its relative distribution is therefore a very important factor in the manufacturing of medical inhalers; as it greatly determines the percentage of a drugs active ingredient that can travel to and penetrate the lungs to arrive at its site of action.[3] An aerosol aerodynamic-particle size distribution (APSD) measurement can therefore be applied in pharmaceutical product development, regulatory reviews and/or batch quality assurance and control as a measure of a drug's efficacy.


An ideal APSD measurement would be optically by advanced microscopy however; this would only give a valuable insight to the physical properties of the aerosol such as particle size and structure. But not the distribution of the aerosol and its kinetic interaction with the pulmonary drug delivery route during inhalation.

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The United States (US) and European Pharmacopoeia (EP) have documented based on extensive research studies that therapeutically effective orally inhaled aerosol particles, should have a particle size of between 1-5µm in order to be safely deposited in the lungs, depending on the part of the lungs that is its site of action.[4]

Figure 2: A diagram showing the different deposition areas in the human pulmonary drug delivery route of an adult

(Image Copyright: Trudell Medical International [4])

Upon inhalation, aerosol particles larger than 5 µm will be largely deposited at the oropharynx (i.e. the back of the throat) and will be swallowed, whilst aerosol particles of less than 1 µm will not travel down to the lungs and may be exhaled. Particles should be approximately about 5µm in diameter to achieve optimum deposition in the central airway region.



Most apparatus or systems used for the measurement of APSD are made up of 4 basic units [4]:

A mouthpiece adapter - Part of the system responsible for the introduction of inhaled pharmaceuticals into the system. It also serves as an integrity seal to the system and mimics the mouth in human pulmonary drug delivery route.

An induction port - Part of the system that serves as an entrance of the aerosol from the mouthpiece to the impactor, fitted at a right angle to mimic the throat in humans.

An impactor - Part of the system can be defined as a stack responsible for separation and collection according to aerosol particle size. It can either be a single or multistage impactor.

A vacuum pump - Part of the system responsible for the aerosol particle flow/movement through the system. It draws the sample from one end to another by vacuum suction and replicates the act of inhalation.

The impactor forms the basis of most analytical systems and is the main part used for the (APSD) measurement. This is because apart from directly measuring the aerodynamic particle size of aerosols, it also provides a means for the recovery and estimation of the active ingredient analysed compound through sample recovery and spectrophotometric analysis; hence estimating the therapeutic dose and drug efficacy.[4]


The mode of operation of a multi-stage cascade impactor is by inertial impaction of a particle within the system. A single nozzle or set of nozzles are present at each stage/stack of the impactor, through which the aerosol sample is drawn. This aerosol flow is directed towards the collection plate for that particular stage. The size of a particle determines how much resistant it will have to the flow through the impactor and hence its impact on the collection plate at that stage. A multi-stage cascade impactor can be made up of between 5-8 different stacks representative of different stages arranged according to decreasing particle size ranging from 0.1 - 9 µm. Each stage is representative of the different possible deposition sites in the pulmonary drug delivery system.

(Image Copyright: Trudell Medical International [4])

Lighter aerosol particles with less resistance that are not collected at one stage will be passed on to the next stage where the process is repeated. At the final stage, any uncollected aerosol particle is then deposited on an 'after/final filter.' Finally, the collection plates are after a successful measurement run and aerosols present on individual plates are recovered using a suitable solvent, and then analysed by high performance liquid chromatography (HPLC) and UV spectrophotometry. High performance liquid chromatography (HPLC) separates and quantifies analytes present within the aerosol, while the UV spectrophotometer uses UV light scattering analysis to count the condensed aerosol particles present at each stage. The data from both HPLC and UV spectrophotometric analysis together serve as the basis of important calculations that determine how much active ingredient arrives at each part of the drug delivery route.

These calculations are of the coarse particle fractions (CPF), particle fine fraction (FPF) and extra-fine particle fraction (EPF) respectively. The most important calculations are the fine particle dose (FPD) which is described as the prescribed dose of an inhaled drug for adequate lung penetrates; and the fine particle fraction (FPF) expressed as a percentage of delivered dose. Both calculations are required for the measurement of an inhaled drug's efficacy and potency.


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There are different types of multi-stage cascade impactors that can be used for APSD measurements however; there are three major impactors that are both documented on the United States and European pharmacopoeia. They are the Andersen Cascade Impactor (ACI), new generation impactor (NGI) and the multistage liquid Impinger (MSLI). The selection of a suitable multi-stage cascade impactor for analysis depends on the sample to be tested and the analytical data required from the test.

B.3.1. Andersen Cascade Impactor (ACI)

The Andersen cascade impactor is one of the first designed and most widely used impactor for APSD measurements. It is a well-established impactor and over the last few years, it has been re-designed with new accessories to accommodate the US and European pharmacopoeia specifications.

Figure 5: A picture of an Andersen Cascade Impactor (ACI)

(Image copyright MSP corporation. http://www.mspcorp.com/InhalerTesting.pdf[2])

The main features of Andersen Cascade Impactors (ACI) include:

8 individual stages with a particle size range of 0.4 - 9µm.

It also has an option of stage 6 and 7 removal to achieve very low resistance at high flow rates. This can also allow for the measurement of particle size of nasal sprays and aerosols.

The system and its accessories are made with the best grade stainless steel, aluminium or titanium to avoid corrosion.

The ACI is a small system and hence has a small footprint within an analytical laboratory.

B.3.2. New Generation Impactor (NGI)

The new generation impactor (NGI) is a high performance impactor designed for and used in many pharmaceutical industries for the testing of nebulizers, metered dosed inhalers, dry powdered inhalers, nasal sprays and aerosols. Its clever design according to the US and European pharmacopoeia specifications, ease of use and accuracy of analysis ensures high productivity and reproducibility of particle size analysis.

Figure 6: A picture of a New Generation Impactor (NGI)

(Image copyright MSP corporation. http://www.mspcorp.com/InhalerTesting.pdf[2])

The main features of New Generation Impactors (NGI) include

NGI's can operate at any flow rate between 15-100L/min and depending on the flow rate, it can accommodate particle size range from 0.24-11.7µm.

It has 7 stages in total with 5 of its stages in the range of 0.54-6.12µm

Its accessories are made with a highly corrosive resistant material and its excellent conductivity means it is unaffected by static.

The collection plate of NGI's is designed with a micro-orifice to greatly reduces the inter-stage particle losses and eliminate the need for the final filter

It is made up of 3 major parts so part or full automation of the system is possible.

B.3.3. Multi-stage Liquid Impinger (MSLI)

The multi-stage liquid Impinger (MSLI) is the first cascade impactor designed specifically for the measurement analysis of inhaler testing. Even though it only offers 5 stages which are not as many stages as the ACI or NGI, it is also a reliable impactor for APSD measurements.

Figure 7: A picture of a Multi-stage Liquid Impinger (MSLI)

(Image copyright MSP corporation. http://www.mspcorp.com/InhalerTesting.pdf[2])

The main features of multi-stage liquid impinger (MSLI) include:

MSLI's can operate between 30-100L/m and can accommodate a particle size range between 1.7 and 13µm

The design of the MSLI allows the collection stages to be kept moist by the presence of a small volume of liquid; precisely trapping the particles and avoiding the problem of particle bounce associated with ACI and NGI impactors. This also ensures no inter-stage particle losses.

The system and its accessories can be made with the best grade stainless steel or titanium to avoid corrosion.


Multi-stage cascade impactors even though widely accepted and documented as a well-established impactor, involve full resolution through its multi-stages and at some stages, little or no particles are collected at the collection bed.

The presence of many different stages can also affect particle impaction and lead to loss of aerosol particles caused by particle deposition on other impactor parts/surfaces within the system.

Instead of collection at the collection plate, some particles may bounce off the plate and be carried wrongly along the flow path down to a lower stage.

One or a combination of two or more factors can make APSD measurements based on multi-stage cascade impactors, very time consuming and labour intensive. Result accuracy, reliability and reproducibility can also be greatly affected.

This therefore encouraged research into the re-design or modification of the multi-stage impactor by pharmaceutical companies for pharmaceutical companies that would ensure a faster particle size measurement and be a lot less labour intensive.

An introduction of abbreviated impactor - based APSD measurements using Fast Screening impactors (FSI), promises a possible solution to this problem.


The abbreviated impactor method using fast screening impactors is the on-going research alternative to the multi-stage cascade impactor. The modifications include fewer stages (mostly 2-stages) with more precise particle ranges (around the therapeutic fine particle dose of 5 µm) to ensure better analytical results. Also flow rates can be set between 28-100L/min and because of fewer stages; semi or full automation is possible. Some presently designed fast screening impactors for abbreviated impactor measurements are as follows:

Copley Fast Screening Andersen Cascade Impactor (C-FSA): A new modification to the Andersen cascade impactor (ACI). It is made up of a 2 stage impactor with a cut-off particle range of 1.0 - 4.7 µm at flow rates of 28.3L/min for metered dose inhalers.

Trudell Fast Screening Andersen Cascade Impactor (T-FSA): Also a 2-stage modification to the Andersen cascade impactor (ACI) and a further modification to the Copley Fast Screening Andersen Cascade Impactor (C-FSA). It includes an inactive or inoperative stage '0' to provide a functional dead space before the first size separation for aerosols with low-volatile species.

Westech Fine Particle Dose (FPD) Impactor: The Westech Fine particle dose impactor is a 2 -stage impactor with a particle cut-off range of 5µm

MSP Fast Screening Impactor (FSI)


The MSP Fast screening impactor (FSI) was designed based on the new generation impactors (NGI) and developed for the determination of abbreviated impactor measurements. It contains an induction port and a fine particle collector that makes it very suitable for reliably achieving fine particle separation, quickly. Its range of insert accessories provide an option of 4.7 µm, 5 µm or 10 µm (for nasal sprays) cut-off particle sizes at flow rates within ranges 28-100L/min.

The MSP FSI has a two stage process where the first stage involves the impingement of large, non-inhalable boluses into a liquid trap. This is subsequently followed by the fine cut impaction stage

Figure 8: Pictures showing an MSP Fast screening Impactor (FSI)

(Image copyright to EPAG. http://www.epag.co.uk/aimworkshop/1%20AIM%20WORKSHOP%20Mitchell%20and%20Copley.pdf)


A Research into the potential benefits of MSP Fast screening impactors (FSI) versus new generation impactors (NGI); was conducted by 7 leading pharmaceutical companies including Aptar Pharma, MSP Corporation, Trudell medical international, Pfizer and Copley scientific and overseen by the European Pharmaceutical Aerosol Group (EPAG). The research involved the use of both types of impactors for APSD analysis of different types of orally inhaled pharmaceuticals.

Figure 9: An image of the MSP Fast screening Impactor (FSI - 1a) and the New generation impactor (NGI - 1b)

(Copyright of Aptar Pharma. http://www.valois.com/admin/pharmacie/publication/fichier/DG12994946184d74b6da41c52.pdf [9])

C.2.1. APSD measurement parameters

The measurement of the fine particle dose of an aerosol estimated around 5 was done using both FSI and NGI impactors. Three consecutive doses of the same batch of orally inhaled pharmaceutical were introduced into each impactor at a flow rate of 35L/min and an inhalation of 2L.

C.2.2. Summary of the Analysed results

The emitted and fine particle dose of FSI was approximately 15microgram higher than that of the NGI.

Both pre-separator bases were then coated uniformly using a 1% v/v solution of glycerol in ethanol. This showed no significant effect on the fine particle fraction calculated.

The sealing integrity of both mouthpiece adapters measured in kPa showed equivalent strengths. Although the air resistance through the new generation impactor (NGI) was slightly higher compared and this can be attributed to the multi-stages involved.

Both impactors had drug losses within the accepted US and European pharmacopeia limits of <5%. However the drug loss within the FSI was slightly less.

Finally, the use of FSI compared to the NGI showed less time was need for the duration of the analysis and per measurement. Also the solvent consumption was considerably less proving FSI was more labour, time and cost efficient.

C.2.3. Results Conclusion

The findings show that a direct comparison was indeed possible and even though some results were similar for the parameters tested, FSI's gave significantly better results than NGI. Also it showed that fast screening impactors can be used with nebulizers and metered dose inhalers to achieve desired results. However, data for the dry powdered inhalers suggest that more research must be done to prove the validity of the method.[11]


The aim of this research is to use research facilities within the 3M pharmaceutical laboratories to conduct enough experiments and analysis relevant data to fully understand AIM-instrumentation kinetics and how they work to achieve rapid reliable results for APSD measurement of Dry powdered inhalers.

It also aims to use this data to construct a comprehensive monograph covering the AIM-based methods for the analysis of all orally inhaled pharmaceuticals and allow for the incorporation of abbreviated impactor measurements (AIM) into official compendial monographs.