TOOLS OF THE TRADE

Analytical techniques are chosenfor their ability to meet specificinformational requirements.Therefore, a good starting point

for a discussion of cascade impaction is theconsideration of how particle size data areused in the development and manufactureof orally inhaled products (OIPs).

The size of the particles or droplets de-livered by an OIP, such as an inhaler or neb-ulizer, directly influences the success, orotherwise, of drug delivery. This is because

size has an impact on in vivo behavior,most specifically on the regional deposi-tion of the drug active within the respira-tory system. When developing inhaledproducts, particle size is therefore manipu-lated or modified to target specific areas ofthe respiratory tract and to ensure efficacy.

In pharmaceutical production, particlesize is also carefully controlled to ensureconsistent end-product performance. De-velopers and manufacturers must confirmthat the particle size being delivered is con-

stant from dose to dose and device to de-vice, and this extends the need for particlesize data right through quality control.

The upper size limit for delivery to thelungs is generally agreed to be around fivemicrons, with particles larger than 10 mi-crons tending not to penetrate beyond themouth and throat; particles less than onemicron are mostly exhaled. The sub-10 mi-cron range is therefore of most interest toanyone investigating pulmonary deposi-tion, either to ensure successful deliveryto the lungs or, in the case of nasal drugdelivery, to prevent it. Various methods canmeet this sizing requirement, but multi-stage cascade impaction has risen to promi-nence because of a unique combination ofadvantages. These include the ability to:

• Fractionate and collect the entire dose,enabling measurement of a particle sizedistribution specifically for the activeingredient (by chemical assay), ratherthan for the formulation as a whole;

•Measure aerodynamic particle size dis-tribution, the metric most closely asso-ciated with in vivo deposition behavior.Aerodynamic particle size is a functionof geometric particle size, density, andshape and defines how a particle be-haves in a moving air stream;

•Provide the required degree of resolu-tion in the particle size range of greatestinterest for inhalation products—fromzero to five microns.

How Does It Work?Multi-stage cascade impactors separate asample on the basis of differences in theinertia of particles, a function of the aero-dynamic particle size and velocity. The im-pactors consist of a series of stages, eachmade up of a plate with a specific nozzle

24 Pharmaceutical Formulation & Quality > October/November 2012

CAPSULEEnsuring the high-quality development and manufacture of all orally inhaled products requires generating aerodynamic particle size data usingcascade impaction. The unique relevance of cascade impaction in this specialty, how the technology works, and its role in the successful appli-cation of inhaled drug delivery technology are explained.

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Cascade Impaction and its Role inInhaled Product DevelopmentManufacturers continue to refine technology to meet modern requirements formore detailed information and greater productivity > By Mark Copley

ANALYTICAL TECHNIQUES

October/November 2012 > Pharmaceutical Formulation & Quality 25

arrangement and a collection surface. Var-ious designs are available, but the ones usedmost widely are the Andersen Cascade Im-pactor and the Next Generation Impactor.

Sample-laden air is drawn into theimpactor sequentially through the stagesat a defined, constant volumetric flow rate(Figure 1). Nozzle size and total nozzle areadecrease with stage number, but flow rateis constant, so the particles acquire pro-gressively higher velocity. At each stage,particles with sufficient inertia breakthrough the lines of flow and impact on thecollection surface, while the rest pass onthrough the instrument. The net result ofthis process is a series of sized samples thatcan then be chemically analyzed, typicallyusing high performance liquid chromatog-raphy, to produce an APSD specifically forthe active ingredient.

As a result of these operating principles,the separation characteristics of a cascadeimpactor depend on both the dimensionsof the instrument and the flow rate throughit. The diameter of the nozzles and othercritical dimensions must be specified,manufactured, and maintained to appro-priate tolerances to ensure correct per-formance. The flow rate used must becarefully selected and controlled to ensurerepresentative and accurate testing.

Testing Inhaled ProductsMetered dose inhalers, dry powder in-halers, and nebulizers all deliver activeingredients to the lungs. Nasal sprays alsofall into the area of inhaled drug delivery,although here the aim is to target the nasalcavity and avoid unwanted deposition inthe lung. Each device has advantages andlimitations, and each works in a differentway. The test set-up for APSD measurementfor all OIPs is broadly similar, but differenttest conditions and, especially, different testflow rates are required to ensure represen-tative testing for each type of device. De-tailed monographs for the testing of inhaledproducts can be found in the United Statesand European Pharmacopoeias.

Metered Dose Inhalers (MDIs)The vast majority of MDIs are pressurized,with dose delivery driven by a propellant.This makes dose dispersion independentof the flow rate applied during testing. A

test flow rate of 28.3 L/min (1 SCFM) isrecommended for all MDIs, because thisis the flow rate at which the Andersen Cas-cade Impactor, the multi-stage cascadeimpactor first used to a significant degreein OIP testing, has well-defined, calibratedperformance. The flow rate varies when us-ing the Next Generation Impactor, which iscalibrated at 30 L/min for convenience.

Dry Powder InhalersIn contrast to MDIs, the majority of DPIsare described as passive, which meansthat the motive force for drug delivery isprovided by the forced inhalation of thepatient. Here it is crucial to apply a testflow rate that reflects in-use conditions, inorder to ensure comparable aerosolizationof the dose. Pharmacopoeial methods arebased on the assumption that a 4 kPa pres-sure drop across the device is representa-tive of the inhalation profile applied by atypical patient.

To establish the appropriate flow ratefor DPI testing, measurements are carriedout to determine the flow rate associatedwith a 4 kPa pressure drop across the de-vice. This means that low-resistance prod-ucts are tested at higher flow rates thanthose with high resistance, with an upperlimit of 100 L/min imposed. Because deliv-ery is associated with a single inhalation,this flow rate is applied for the time neces-sary to draw a total volume of 4L (2L is rec-ommended by FDA guidance), which isconsidered broadly equivalent to the in-

spiratory volume of an adult. For exam-ple, if test flow rate is determined to be 60L/min, that flow rate is applied as a squarewave function for a duration of four sec-onds to measure APSD.

NebulizersDose delivery test methods for nebulizershave recently been revised and now spec-ify testing via the application of sinusoidalflow profiles simulating tidal breathingconditions. Profile specifications are de-fined according to the target user group:adult, child, infant, and neonate. How-ever, because cascade impactors must beoperated with a constant flow rate, a testflow rate of 15 L/min is specified for APSDmeasurement, based on the mid-inhala-tion flow rate of a typical adult user. TheNext Generation Impactor has calibratedperformance at this relatively low flow rateand is therefore especially useful for thisimportant class of OIPs. Cooling of theimpactor may also be necessary in somecases to mitigate heat transfer-relateddroplet evaporation.

Nasal SpraysIn sharp contrast to OIP testing, multi-stagecascade impaction is used for nasal spraycharacterization, where the goals are to as-sess and limit the extent of pulmonary drugdeposition. Like MDIs, the test flow rate ap-plied has no direct impact on dose disper-sion and is set at a standard 28.3 L/min.

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(Continued on p. 26)

Figure 1.

An Andersen CascadeImpactor withschematics showinghow air flows throughthe instrument andthrough individualstage nozzles.

26 Pharmaceutical Formulation & Quality > October/November 2012

However, testing is carried out using an ap-propriately sized expansion chamber ofone, two, or five liters to ensure that thedose is adequately dispersed and effec-tively drawn into the impactor. Used in thisway, multi-stage cascade impaction sup-ports the reduction—or, in the case of gener-ics, matching—of the fines tail of nasal sprayproducts.

Multi-stage cascade impaction is apivotal analytical instrument for charac-terizing inhaled products, with associatedtest methods designed to provide an ac-ceptable in vitro representation of in vivobehavior for each device type and a rugged,reproducible quality control tool. The cen-trality of the technique makes it a focus forongoing development, and, today, bothequipment and methodologies are under

intense scrutiny as leading researchersconsider how best to fashion cascade im-paction to meet modern requirements formore detailed information and greaterproductivity. These developmental efforts,in combination with the intrinsic advan-tages of cascade impaction, will ensurethat this technology retains its value andrelevance for inhaled product testing longinto the future. n

TOOLS OF THE TRADE | ANALYTICAL TECHNIQUES

Mark Copley is sales director atCopley Scientific. He can be reached atm.copley@copleyscientific.co.uk.

Editor’s Choice1. Copley M. Understanding cascade impaction and its importance for inhaler testing. July 2007. Available at:http://www.copleyscientific.com/documents/ww/Understanding%20Cascade%20Impaction%20White%20Paper.pdf.Accessed October 19, 2012.

2. Friebel C, Steckel H, Müller BW. Rational design of a dry powder inhaler: device design and optimisation. J Pharm Pharmacol.2012;64(9):1303-1315.

3. Tougas TP, Christopher D, Mitchell J, et al. Product lifecycle approach to cascade impaction measurements. AAPS PharmSciTech.2011;12(1):312-322.

4. Taki M, Marriott C, Zeng XM, Martin GP. Aerodynamic deposition of combination dry powder inhaler formulations in vitro: acomparison of three impactors. Int J Pharm. 2010;388(1-2):40-51.

5. Solomita M, Smaldone GC. Reconciliation of cascade impaction during wet nebulization. J Aerosol Med Pulm Drug Deliv.2009;22(1):11-18.

(Continued from p. 25)

In sharp contrastto OIP testing,multi-stagecascade impactionis used for nasalspray characteri-zation, where thegoals are to assessand limit theextent of pulmonary drugdeposition.

Figure 2.

The Next Generation Impactor was developed specifically for pharmaceutical applications andcommercialized at the beginning of the last decade.