Time-of-Flight Methods for the Measurement of the Aerodynamic Particle Size Distribution of Aerosols from Orally Inhaled Products Points to Consider

Time-of-Flight Methods for the Measurement of the Aerodynamic Particle Size Distribution of Aerosols from Orally Inhaled Products: Points to Consider Jolyon Mitchell Jolyon Mitchell Inhaler Consulting Services Inc., 1154 St Anthony Road, London, Canada, N6H 2R1 Summary Background: Particle time-of-flight (TOF) methods rapidly determine the number-weighted aerodynamic particle size distribution (APSD) of aerosols from 0.3 to >20 μm aerodynamic diameter from all classes of orally inhaled product (OIP) Software is then used to calculate the mass-weighted APSD which should be equivalent to that obtained by the slower and substantially more complicated-to-use cascade impactor (CI) methods recommended in the pharmacopoeial compendia Methods: We review this choice of techniques to obtain APSD-related information during the OIP life cycle, where there is regulatory freedom to so We also examine considerations concerning TOF- versus CI-based APSD determination for the different classes of OIP Results: A serious drawback to TOF analysis has been the lack of a chemical assay for the active pharmaceutical ingredient(s) in the size-characterized particles However, this limitation may be about to be overcome if TOF analysis is combined with single particle mass spectrometry, developed originally for bioaerosol detection and size-categorization The correlation of measures of clinically important fine particle mass (FPM) by TOF- and CI-based analyses can be achieved by the simultaneous measurement of this metric using a single-stage abbreviated impactor add-on supplied by the manufacturer of the most frequently encountered TOF analyzer Conclusions: Users need to consider several potential sources of bias with TOF analysis, in particular distortion of droplets > μm diameter, deviations in particle density and shape from unit density microspheres, and increased statistical ‘noise’ associated with the number-to-mass weighting conversion Introduction Particle time-of-flight (TOF) methods rapidly determine the number-weighted aerodynamic particle size distribution (APSD) of aerosols from about 0.3 to 30 μm aerodynamic diameter from all classes of orally inhaled product (OIP) [1, 2] The basic principle of operation is illustrated in Figure Figure 1: Schematic of TOF analyzer based on the APS® Aerosol Spectrometer® (TSI Corp., St Paul, MN) Methods: After passing through an inlet followed by a controlled dilution stage, incoming particles are accelerated singly through a well-defined flow field in the measurement zone of the analyzer, in which the particles experience ultraStokesian acceleration [3] The transit time of the particle between two well-defined locations in the measurement zone is a monotonic function of aerodynamic diameter; light scattering signals operates the timing process Longer times are associated with larger-sized particles due to the enhanced drag they experience in the accelerating flow field [4] The APS® Aerosol Spectrometer® (TSI Inc., St Paul, MN, USA) is the most likely to be encountered TOF analyzer [5] This equipment has been through several evolutions since it was introduced just under 30 years ago [6], with the current version being the model 3321 The E-SPART TOF analyzer, developed at the University of Arkansas, has similar aerodynamic particle sizing characteristics [7], but is more of a research tool than a readily available commercial instrument The Aerosizer ® series of TOF analyzers is obsolete, but may still be encountered Results Table is a summary of the considerations that should be given when exploring the potential of this method is provided in Table 1, together with comparative information for the full resolution CI method Table 1: Comparison between TOF and CI-Based Measurements for OIP Aerosol APSD Assessment Factor to Consider Simplicity for the operator? Typical measurement range and size resolution? Rapidity per measurement? Number-to-mass weighting conversion? Corrections for more than one particle in measurement zone simultaneously and ‘phantom particles API assay? Suitability for aqueous droplet-based formulations? Suitability for highly porous particles? Suitability for nonspherical particles TOF Analysis Highly simple once a standard operating procedure has been established; complexity is built into the instrument itself 0.5 to 20 μm aerodynamic diameter, with resolution of 0.02 μm and 0.03 μm at 1.0 μm and 10 μm size limits Between 30 s and 60 s Yes – may result in statistical noise at large end of APSD; sample time is important to assess a representative population of particles CI Analysis Many steps that must be followed rigorously; easy to make mistakes; complexity is associated with the method rather than the apparatus 0.4 to 10 μm aerodynamic diameter; resolution no more than sizes between 0.5 and 5.0 μm aerodynamic diameter As much as hours for full resolution CI; abbreviated impactor measurements increase rapidity No – but sample time needs to be long enough to capture enough mass of API for meaningful assay on stages away from the mode of the APSD Yes – current hardware and software for most widely available TOF system is designed to minimize bias from these causes No – impactors can sample aerosol concentrations much greater than encountered with OIPs without particle-particle interactions Not without additional technique such as single particle mass spectrometry Yes – requires development and validation of an appropriate method for each API present Questionable if droplet size exceeds about 5.0 μm, since some distortion can occur in the ultra-Stokesian motion at measurement Questionable, as deviations below the reference condition for the aerodynamic size scale (1.03 kg/m3) may cause underestimation of aerodynamic diameter Questionable, as increases in dynamic shape factor from unity (spherical) can result in an underestimation of aerodynamic diameter Yes – as long as precautions are taken to control heat transfer from the CI to the aerosol Yes – no correction is necessary as particle motion is in the Stokesian regime Yes – no correction is necessary as particle motion is in the Stokesian regime Discussion At first sight, TOF analysis of OIP-generated aerosols is a highly attractive prospect, given the rapidity and high resolution of this measurement method Indeed, there have been many studies involving each of the major classes of OIPs, from pressurized metered dose inhalers (pMDIs) without [8, 9] and with holding chamber add-on devices [10]; dry powder inhalers (DPIs) [11, 12] and less frequently with nebulizing systems [14] TOF-based APSD analysis has clear advantages compared with the CI method, considering ease of use for the operator, measurement range, size resolution and measurement duration However, the following six considerations demonstrate the potential drawbacks associated with the TOF-based approach The following observations are pertinent, taking each of these considerations in turn: A B C D E F Number-to-mass weighting conversion: Transformation of the TOF instrument-measured APSD from its native number- to a mass-weighted basis for direct comparison with CI/MSLI-based measurements will amplify random variability arising from the few particles always present with polydisperse aerosols typically produced by OIPs at the large extreme of the APSD [1] Extending the sampling time to minimize such variability should therefore be considered as part of method development Correction for more than one particle in measurement zone simultaneously (particle coincidence) and ‘phantom’ particles: The ‘double-crest’ light scattering detection and tracking technology associated with the current APS® aerosol spectrometer® [14] has greatly improved the problem of particle coincidence and ‘phantom’ particle creation in the measurement zone [15] that restricted the use of earlier TOF analyzers with the concentrated aerosols frequently encountered with OIPs Nevertheless, it is prudent to check the shape of the APSD for anomalies that might be indicative of an excessively high particle concentration during method development As many as two additional dilution stages for use with the APS® aerosol spectrometer® and operated in tandem are capable of reducing the aerosol concentration by as much as 10,000:1 API assay: The lack of a direct assay for API is a significant limitation However, two possibilities exist having potential to overcome the problem: (1) if working with an APS ® aerosol spectrometer®, utilize the single-stage impactor with USP/Ph.Eur option to obtain measures of fine particle mass fraction that can in turn be compared with full resolution CI-generated data in order to validate the TOF-generated APSD [16, 17]; (2) investigate the use of tandem single particle mass spectrometry (SPAMS), in which the particles are assayed immediately after passing through the TOF measurement zone [18, 19] Suitability for aqueous droplet-based formulations: In principle, TOF analysis should be suitable as long as precautions are taken to control evaporation- or condensation-related bias However, there is evidence from studies with monodisperse oil droplets that distortion from sphericity can occur for sizes larger than about μm aerodynamic diameter [20] Again, comparison of TOF- and CI-determined APSDs for the same product should resolve any concerns Suitability for highly porous particles: Experiments sampling monodisperse aerosols have shown particle density-related bias results in an overestimation of aerodynamic diameter by TOF analyzer by 10-15% in the range from 1.05 to 2.30 x 10 kg m-3 [21] It is likely that this bias persists for densities < 103 kg m-3 (the reference density for the aerodynamic size scale), so that care is needed when working with highly porous particles, that are becoming of increasing importance for the delivery of APIs by dry powder inhaler platform [22] Suitability for non-spherical particles: Studies with monodisperse single crystals of different sizes having controlled dynamic shape factors (χ) close to 1.18 (χ = 1.00 for a perfect sphere) have shown that the APS® aerosol spectrometer®-measured aerodynamic diameter can be undersized by between 20 to 27% [23] Most particles emitted by pMDI and DPI products are non-spherical, so comparison of TOF- and CI-determined APSDs for the product of interest should be considered as a key component of method development Conclusions Measurement of OIP aerosol APSD by TOF analysis is an attractive proposition, especially with the advent of combined TOF-SPAMS systems that have the potential to link the size distribution unambiguously to API content However, users also need to consider several potential sources of bias with these system; in particular particle coincidence in the measurement zone, deviations in particle density and shape from unit density microspheres, and increased statistical ‘noise’ associated with the number-to-mass weighting conversion A comprehensive method development strategy is therefore advocated, in which TOF-based measurements are compared with those derived from CI-analysis The single stage impactor add-on for the APS® aerosol spectrometer® can provide a useful way to bridge these measurements in terms of the clinically important fine particle mass fraction References 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Mitchell JP, Nagel MW: Time-of-flight aerodynamic particle size analyzers: their use and limitations for the evaluation of medical aerosols J Aerosol Med 1999;12(4):217–240 Mitchell JP, Nagel MW: Particle size analysis of aerosols from medicinal inhalers KONA Powder and Particle 2004;22:32-65 Baron PA, Mazumder MK, Cheng YS: Direct-reading techniques using optical particle detection In: K Willeke, PA Baron, (eds) Aerosol Measurement: Principles, Techniques and Applications, 2nd Edition Van Nostrand Reinhold , NY, USA; pp 495-535, 2001 Chen BT, Cheng YS, Yeh HC: Performance of a TSI aerodynamic particle sizer Aerosol Sci Technol 1985;4(1):89–97 Beck TJ: A new time-of-flight spectrometer for aerodynamic size measurement of MDIs and powder inhalers In: P.R Byron, R.N Dalby, and S.J Farr, (eds) Respiratory Drug Delivery V InterPharm Press, Buffalo Grove, IL, pp 306, 1996 Remiarz RJ, Agarwal JK, Quant FR, Sem GJ: Real-time aerodynamic particle size analyzer In V.A Marple, and B.Y.H Liu, (eds) Aerosols in the Mining and Industrial Work Environments, Volume Ann Arbor Science, Ann Arbor, MI, USA; pp 879-895, 1983 Saini D, Biris AS, Srirama PK, Mazumder MK: Particle size and charge distribution analysis of pharmaceutical aerosols generated by inhalers Pharm Dev Technol 2007;12(1):35-41 Stein SW, Myrdal PB: The relative influence of atomization and evaporation on metered dose inhaler drug delivery efficiency Aerosol Sci Technol 2006;40(5):335–347 Harris J, Stein SW, Myrdal PB: Evaluation of the TSI Aerosol Impactor 3306/3321 system using a redesigned impactor stage with solution and suspension metered-dose inhalers AAPS PharmSciTech 2006; 7(1): Article 20 Mitchell JP, Nagel MW, Cheng YS: Use of the Aerosizer® aerodynamic particle size analyzer to characterize aerosols from pressurized metered dose inhalers for medication delivery J Aerosol Sci 1999;30(4):467-477 Schultz-Fademrecht T, Bechtold-Peters K, Fuhrherr R, Garidel P: Characterization of aerodynamic behaviour of spray dried protein powders by TSI Aerodynamic Particle Sizer and by Andersen Cascade Impactor In: RN Dalby, PR Byron, J Peart, JD Suman and SJ Farr, (eds) Respiratory Drug Delivery 2004, Davis Healthcare Int Publ., River Grove, Il, USA; pp 381-384, 2004 Svensson M: High throughput inhaler testing III: Modified aerodynamic particle sizer set-up for DPIs In: RN Dalby, PR Byron, J Peart, JD Suman and SJ Farr, (eds) Respiratory Drug Delivery 2006, Davis Healthcare Int Publ., River Grove, Il, USA; pp 475-477, 2006 Frølund L, Poulsen LK, Heinig JH, Svendsen UG, Madsen F: Immunological and physical properties of allergen solutions Allergy 1991;46(1):1-9 Hairston PP, Dormán FD, Sem GJ, Agarwal JK: Apparatus for measuring particle sizes and velocities U.S Patent 5,561,515 US Patent and Trademark Office, Washington, DC 1996 Heitbrink W A Baron P A, Willeke: Coincidence in time-of-flight aerosol spectrometers: Phantom particle creation Aerosol Sci Technol 1991;14(1):112-126 Mitchell JP, Nagel MW, Wiersema JK Doyle CC: Aerodynamic Particle Size Analysis of metered dose inhalers: Comparison of Andersen 8-stage cascade impactor, Next Generation Pharmaceutical Impactor, and Model 3321 Aerodynamic Particle Sizer aerosol spectrometer,” AAPS PharmSciTech 2003;4(4) Article 54 Stein SW, Gabrio BJ, Oberreit DR, Hairston PP, Myrdal PB, Beck TJ: An evaluation of mass-weighted size distribution measurements with the Model 3320 Aerodynamic Particle Sizer Aerosol Sci Technol 2002;36(7),845-854 Susz A, Morrical BD, Fergenson DP: New determination method of aerodynamic diameter size distribution in dry powder inhalers using SPAMS 3.0 In: Dalby RN, Byron PR, Peart J, Suman JD, Traini D and Young PM, (eds) Respiratory Drug Delivery 2014, Davis Healthcare International Publishing LLC, River Grove, Illinois, USA; pp 515-518, 2014 New A, Prime D, Zomer S, Elder D, Donovan R, Freney E: Detection and assessment of co-association in inhalable drug particles using aerosol time-of-flight mass spectrometry, Rapid Comm Mass Spectrom 2008;22(23):3873-3882 Griffiths W D, Iles PJ, Vaughan NP: The behavior of liquid droplets in an APS3300 J Aerosol Sci 1986;17(6):921-930 Cheng YS, Chen BT, Yeh H-S: Performance of an aerodynamic particle sizer Appl Occup Environ Hyg 1993;8(4):307-312 Frijlink HW, de Boer AH: Dry powder inhalers for pulmonary drug delivery Expert Opin Drug Deliv 2004;1(1):67-86 Marshall IA, Mitchell JP, Griffiths WD: The behavior of regular-shaped non-spherical particles in a TSI aerodynamic particle sizer J Aerosol Sci 1991;22(1):73-89  ... with the advent of combined TOF-SPAMS systems that have the potential to link the size distribution unambiguously to API content However, users also need to consider several potential sources of. .. Table 1, together with comparative information for the full resolution CI method Table 1: Comparison between TOF and CI-Based Measurements for OIP Aerosol APSD Assessment Factor to Consider Simplicity... [14] TOF-based APSD analysis has clear advantages compared with the CI method, considering ease of use for the operator, measurement range, size resolution and measurement duration However, the