Abstract

Plume geometry of pressurized metered dose inhalers (pMDIs) is a macroscopic aerosol characteristic dependent on the combination of formulation and device [1, 2]. High-speed laser Imaging (HSLI) has been the preferred technique to characterize the geometry of the plume because of its non-invasive sampling approach and relatively fast data collection system [1, 3]. However, it has been reported that even though image processing may remove bias to a certain extent, laser image techniques remain subjective when identifying the edge of the aerosol plume and therefore the plume angle [4-6]. Plume Induction Port Evaluator (PIPE) is an attachment for cascade impactors that allows calculation of the plume angle by drug mass quantification, rather than by laser light illumination (Figure 1). The method does not rely on proprietary software and can be used while performing aerodynamic characterization, expanding the use of cascade impactors. The objective of this study was to investigate the capabilities of the new mass-based plume angle analysis to differentiate between three commercial pMDI suspension products (Ventolin ® HFA, ProAir ® HFA, and Proventil ® HFA). It is expected that development of this new characterization technique may provide a suitable method to evaluate the equivalence of aerosol performance in generic products. Method PIPE is a 3D printed segmented induction port designed to map the deposition patterns of the aerosols emitted by orally inhaled products (OIPs) (Figure 1). Briefly, plume angles of a pMDI can be expressed as the effective angle formed between the inner surface of the four sections in PIPE (i.e., section 1 is Top1 segment plus Bottom1 segment) and the elbow piece, respect to the aerosol source. The log-normally distributed deposition patterns in PIPE will be used to calculate the effective angle of a plume where fifty percent of the drug deposits in the induction port. Such angle will receive the denomination of Mass Median Plume Angle (MMPA). Figure 1. a) 3D printed Plume Induction Port Evaluator connected a Next Generation Impactor; b) The segmented induction port design composed of three main pieces: An initial cylinder that can be disassembled in eight segments, a ninety-degree (elbow) connector and a non-segmented secondary cylinder (Throat) Plume angles of albuterol sulfate pMDIs products will be evaluated using both, mass and laser-based techniques. For laser imaging, cross-sectional images of the plume were captured at 400 frames per second using a high-speed monochromatic camera (Flea3®,Pointgrey), a laser source (532nm, 200mW Laser module, Direct Voltage) and a laser line generating lens (45° Fan angle, Thorlabs Inc.). Analysis of the aerosol edge from a composite image was used to calculate the angle of the plumes using the software ImageJ. Deposition patterns from pMDIs were evaluated in absence and presence of airflow to calculate MMPAs. Albuterol sulfate was collected using phosphoric acid 0.1% (v/v) and assessed by High-Performance Liquid Chromatography (HPLC). pMDIs were manually actuated manually twice after shaking for five seconds. Experiments were conducted in triplicate. T wo-way ANOVA analysis (p<0.05) followed by the post-hoc Tukey’s multiple comparison was performed to evaluate the statistical difference between the plume angles using the software JMP®10.0.2. RESULTS AND DISCUSSION Three albuterol sulfate suspension based pMDIs were tested on PIPE and a high-speed laser imaging system. The objective of the study was to investigate if MMPA is a suitable metric capable of differentiating between aerosols generated by commercially available albuterol sulfate products. Figure 1 shows examples of composite images of the plumes emitted by the studied pMDI products during the HSLI analysis. Figure 1. Cross-sectional images of three marketed pMDI products obtained by High-Speed Laser Imaging (HSLI) Summary of angle measurements is presented in Table 1. Results obtained by PIPE show a reduction of plume angle when comparing MMPA results, in absence and presence of airflow. These results demonstrated that plume geometry is significantly affected by airflow, and therefore it should be characterized considering the patient inhalation. Table 1. Plume Angles Calculated from Plume Induction Port Evaluator (PIPE) (n=3) and High-Speed Laser Imaging (HSLI) (n=10) Plume angles obtained by HSLI presented lower values compared to the mass-based approach. However, the rank order of the plume angles obtained by mass was in good agreement with laser light sheet method in absence and presence of airflow. Conclusions PIPE offers an alternative to laser-based characterization methods to evaluate the plume angle of OIPs, based on reliable drug quantitation while simulating patient inhalation. The method proved to be sensitive in differentiating marketed albuterol sulfate pMDI products, with lower variability than laser imaging and following the same rank order. Therefore, highly reproducible results for MMPA makes PIPE a robust analytical tool, capable of comparing products with similar formulations but different macroscopic aerosol characteristics.