(T1030-08-44) Effect of Coating of Andersen Cascade Impactor and Next Generation Impactor on the Aerodynamic Particle Size Distribution of Nine Commercial Metered Dose Inhalers

Purpose: The aerodynamic particle size distribution (APSD) measurements of metered dose inhalers (MDIs) are a key component for formulation and product development, quality control, and for the in vitro assessment of bioequivalence between a branded and generic product. Evaluation of the APSD parameters is performed using one of the two pharmacopeial impactors: Andersen Cascade Impactor (ACI) and Next Generation Impactor (NGI). Typically, coating of different stages of an impactor with a material such as silicone is considered for dry powder inhalers (DPIs) to reduce the risk for particle bounce but is not generally utilized for MDIs. Differences in APSD measurements were previously noted for commercial MDIs due to coating of the NGI impactor stages [1]. To investigate whether coating of the impactor stages should be considered for solution and suspension MDIs, this study expanded on the previous work by assessing the effect of coating of ACI stages on the APSD measurements of 9 commercial MDI products and compared the effect of stage coating between an ACI and NGI.

Methods: Nine solution and suspension MDI products commercially available in the United States were utilized for this study (Table 1). The flow rate was set at 28.3 liters per minute (LPM) for the ACI and 30 LPM for the NGI. The stage coating was composed of a solution consisting of 40 g glycerol and 10 ml of a mixture comprised of 15 g Brij-35 in 100 ml of 96% ethanol, as previously described [1]. One canister of each MDI was tested in triplicate using an ACI and NGI, with and without coating. The USP inlet was not coated. For all 9 MDI products, there were 6 actuations fired into the impactors. The NGI and ACI delivered dose was determined as the sum of active pharmaceutical ingredient (API) collected from the entire apparatus (USP induction port to filter). Fine particle dose (FPD) was determined by linear interpolation of the cumulative distribution function for particles less than 5 µm and 1 µm. Fine particle fraction < 5 µm (FPF5) and FPF < 1 µm (FPF1) were determined by normalizing the respective FPDs to the delivered dose. Mass median aerodynamic diameter (MMAD) was determined using a log probability vs. log size plot. A statistical model built in RStudio using the MDI product, impactor type and coating, and their interaction as effect factors in an analysis of variance (ANOVA) model was evaluated to distinguish effects of impactor type and coating.

Results: Figure 1 shows the effect by coating vs. aerodynamic particle size for each product using an ACI. As shown in the figure, the effect of coating was evident at the later stages of the ACI for particles < 2 µm, with the size of the effect increasing with decreasing size. Figure 2 shows the FPF1, and MMAD measurements from the ACI and NGI, as a ratio of coated to uncoated impactor for the 9 commercial MDI products. A coated/uncoated ratio greater than 1 indicates that the measurements increase with coating; while a coated/uncoated ratio less than 1 indicates that measurements decrease with coating. Coating significantly decreased small fines (FPF1, p< 0.05), and increased aerodynamic particle size (MMAD, p < 0.05) as compared to when the stages were uncoated. This was observed by 19 of 24 samples having a coated/uncoated ratio of less than 1 for FPF1 and 18 of 24 samples having a coated/uncoated ratio greater than 1 for MMAD. More products showed a significantly higher MMAD as a result of coating for an NGI than the ACI. The effects of coating on FPF5 appeared to be product-dependent and were not significant (p >0.05). While our previous results with the NGI suggested that coating has more significant effects on suspension MDIs as compared to solution MDIs [1], this study using an ACI suggested that the effect of coating appeared to be unrelated to the formulation type.

Conclusion: Impactor coating showed significant effects on FPF1 and MMAD, but not on FPF5, indicating that coating may influence smaller particulates and reduce the amount of respirable small fines while maintaining the respirable fraction (FPF5) relatively unchanged. The data suggest that coating may prevent the particle bounce in case of superfine particles for MDIs.

References: 1. Sandell, D., Svensson, M., Conti, D., Sheth, P., Oguntimein, O., Bielski, E., Bulitta, J., Hochhaus, G: Coating Stages of Next Generation Impactor (NGI) When Testing Metered Dose Inhalers (MDIs) – A Comparative Study on US Commercial MDI Products. In RDD 2020. Edited by Dalby RN and Peart J. 2020: 463-468.

Acknowledgements: Funding for this work was made possible, in part, by the U.S. Food and Drug Administration through Contract 75F40119C10154 and Grant U01FD004943. Abhinav Mohan was supported by a fellowship program administered by the Oak Ridge Institute for Science and Education (ORISE) through an interagency agreement between the U.S. Department of Energy and the U.S. FDA. The views expressed in this abstract are from the authors only and do not necessarily reflect the official policies of the Department of Health and Human Services, nor does any mention of trade names, commercial practices, or organization imply endorsement by the United States Government.


Table 1: Commercial MDI products evaluated in the current study


Figure 1: Coating effect vs. aerodynamic particle size. Data: ratio of the mean of triplicate runs. FP: Fluticasone propionate; SX: Salmeterol xinafoate; FF: Formoterol fumarate; GP: Glycopyrrolate; BUD: Budesonide. The Andersen Cascade Impactor stage cutoff values (µm) are shown in the x-axis.


Figure 2: Ratio of coated to uncoated A) FPF1, and B) MMAD of 9 commercial MDI products identified in Table 1. Data: ratio of the mean of triplicate runs. FP: Fluticasone propionate; SX: Salmeterol xinafoate; FF: Formoterol fumarate; GP: Glycopyrrolate; BUD: Budesonide. FPF5: fine particle fraction < 5 μm; FPF1: fine particle fraction < 1 μm; MMAD: mass median aerodynamic diameter. ACI: Andersen Cascade Impactor; NGI: Next Generation Impactor. Dotted line represents a coated to uncoated ratio of 1 indicating no change.