Abstract

Characterization of the plume geometry for pressurized metered dose inhalers (pMDIs) is typically performed using high-speed laser imaging (HSLI). However, the method does not allow for simulation of inhalation airflow and does not rely on drug mass quantification [1, 2]. To address these limitations, in this study a novel analytical method is described: the plume induction port evaluator (PIPE). PIPE characterizes the plume geometry of pMDIs from their mass deposition patterns and the effective angle created between its sections and the nozzle. The method is easily adaptable to current aerosol characterization instruments (i.e. can be used directly with impactor based methods), has comparable calculations workflow methods, and can be used under airflow conditions, simulating inhalation flows. The objective of this study was to investigate the effect of airflow on the geometry of a plume emitted by a solution pMDI using mass-based plume analysis. It is proposed that the PIPE can allow for better understanding of pMDI plume geometry during inhalation, while expanding the data sets that can be obtained during cascade impactor testing. Method PIPE is a segmented induction port designed in Autodesk Inventor 2017 and prototyped in aluminum by the department of Mechanical Engineering at The University of Texas at Austin. Its geometry considers the inner dimensions of the current USP induction port [3] to prevent variations in recirculation regions and therefore deposition patterns (Figure 1). Figure 1. a) Design of the Plume Induction Port Evaluator (PIPE); b) PIPE connected to a Next generation cascade impactor. Plume angles can be determined following actuation of the pMDI into the PIPE (analogous to the USP induction port) and drug deposited on each segment of the apparatus can be collected. From this data, the Mass Median Plume Angle (MMPA), a novel characterization parameter that describes the effective angle of a plume where fifty percent of the drug deposits in the induction port, can be calculated. To calculate MMPA the Probit method, traditionally used to calculate Mass Median Aerodynamic Diameter (MMAD) in cascade impactors [4], was used. Effective angles for each segment of PIPE were calculated as the median angle achieved between the limits of the segments (individual parts of PIPE) at each section (the combination of “top” and “bottom” as shown Figure 1) with respect to the pMDI nozzle. Droplets deposited on the mouthpiece adapter were calculated to have an angle greater than 53°. Investigation of the effect of air flow on the plume angle of a solution pMDI was performed using PIPE attached to a NGI operated at 15, 30, 60, and 90 L/min. Rhodamine B was used as a soluble drug model (0.01% w/w), dissolved in ethanol (2.49 % w/w) and HFA134a (97.5% w/w) used as the liquid propellant. Ethanol/water solution (1:1) was used to collect the fluorescent dye from the PIPE apparatus. The fluorescent dye was assayed by fluorescence spectroscopy using a wavelength of 550 nm excitation and 610 nm emission. The pMDI actuator used had an orifice diameter of 0.7 mm, and crimped metered valve had a total volume of 63µL. Each experimental condition was tested in triplicates using the same actuator. RESULTS AND DISCUSSION Deposition patterns in PIPE were found to be log-normal distributed and highly reproducible (%CV less than 4%). Illustrative cumulative distributions are summarized in Figure 2. As the flow rate was increased, a significant decrease in mouthpiece adapter (>53°) deposition was observed. In addition, a decrease in drug deposition on the first section of PIPE (Top1+Bottom 1, median angle = 46°) was observed. A shift in the deposition patterns toward the elbow was observed as flow rates increases and these changes were statistically significant between all tested airflow conditions. Figure 2. Deposition patterns on mouthpiece adapter (>53°), PIPE sections (12.85° - 45.85°) and elbow (5.45°). Deposition patterns show an increase in drug deposited at the distal areas of the induction port as flow rate increases. Analysis of the deposition patterns at each segment, i.e. the top versus bottom segments, indicated that the plumes were upward oriented for all tested conditions. Plume angles were calculated from deposition patterns in PIPE by using the Probit method. PIPE data in Table 1 illustrated an inverse correlation between flow rate and mass median plume angles (p < 0.05, ANOVA/ Tukey test). Table 1. Effect of flow rate on the Mass Median Plume Angle (MMPA), n=3 Flow rate (L/min) Mass Median Plume Angle (°) ± SD 15 41.34 ± 0.2 30 38.41 ± 1.11 60 35.71 ± 0.47 90 32.11 ± 0.34 Conclusions PIPE was connected to a cascade impactor operating at different flow rates to evaluate the effect of the inhalation on the plume geometry of solution pMDIs. Mass based plume angles showed a significant decrease as flow rate increases, which demonstrate that this parameter should likely be evaluated under airflow conditions. Deposition patterns in the segmented induction port generated by solution-based pMDIs were log-normal distributed and highly reproducible. Therefore, calculations of plume angle based on mass is a reliable approach that can be used to evaluate the effect of airflow on solution based pMDIs.