Abstract

Title: Investigation of the Influence of Temperature and Formulation on Deposition Patterns from Solution pMDIs using a High-Resolution Induction Port Authors: Daniel Moraga-Espinozaa,c , Eli Eshaghianb and Hugh D.C.Smytha Affiliation: a) department of Molecular Pharmaceutics and drug delivery, College of pharmacy, University of Texas at Austin, Austin, Texas , b) College of natural sciences, University of Texas at Austin, Austin, Texas , c) Escuela de Farmacia , Universidad Valparaiso, Valparaiso, Chile. Purpose: Non-impaction methods such as laser diffraction and high-speed laser imaging are widely used to characterize the plume of metered dose inhalers (pMDIs) at the beginning of the aerosolization process. However, these techniques lack a means to restrict the plume path and do not apply airflow, both of which are necessary to understand drug deposition in the mouth/throat. The objective of this study was to design a high-resolution induction port (HRIP) compatible with cascade impactors to allow for the quantification of drug deposited within a USP induction port , thereby increasing the scope of conventional cascade impaction methods and providing a greater understanding of pMDI plume deposition. To achieve these aims, the influence of pMDI formulation and ambient temperatures on plume geometry was evaluated through analysis of spray deposition patterns within the HRIP. Methods: The high-resolution induction port (HRIP) was designed in Autodesk Inventor 2017 and prototyped with a 3D printer (Viper si2TM) based on stereolithography technology. The material employed in the prototype was ProtoThermTM 12120, a liquid photoreactive polymer with high tolerance to temperature and water-resistant. To generate different deposition patterns, we prepared three formulations using Rhodamine B as a soluble model drug (0.01% w/w) in pMDI formulations containing three different ethanol concentrations with HFA134a as the propellant. Relevant ambient temperatures were simulated by letting the canisters equilibrate in a refrigerator (~ 4⁰C), or by connecting a heating tape to the cannister for one hour prior to actuation. Each pMDI device had a 28 µL metered valve and an actuator with a 0.3 mm orifice diameter. Particle size analysis of the plume was done by laser diffraction using a Sympatec HELOS-R system. The inhaler was positioned at a fixed height such that the orifice of the nozzle was aligned relative to the laser path. The mouthpiece was positioned at different distances from the laser matching the center point of the HRIP segments. Data acquisition was set to 50 milliseconds before the optical concentration (OC) reached 1%, with a time base of 5 milliseconds using Fraunhofer theory during the study. The plume geometry of each formulation was measured by using a high-speed monochromatic camera and a laser sheet to illuminate the droplets of the aerosol. The camera was set up perpendicular to the laser sheet plane so the complete aerosol mist can be visualized. Plume angles were calculated from a composite image of the plume, analyzing the edges of the aerosol mist using the software ImageJ. Two-way ANOVA analysis (p<0.05) followed by the post-hoc Tukey’s multiple comparison was performed to evaluate statistical difference between the plume angles using the software JMP®10.0.2. Results: The increment in ethanol concentration not only increased droplet size but also increased the plume angle significantly. Similarly, it was found that decreasing the temperature has a statistically significant effect on increasing droplet size and plume angles as well. This data correlates with the deposition maps generated by HRIP showing that plumes with larger angles had increments of drug deposited on the bottom segments 2-4 cm from the actuator mouthpiece. These results correlate with the composited images of the plumes which are projected slightly downward at all tested conditions. Conclusion: The HRIP is a chemical assay-based method developed to help to understand how solution pMDI systems are affected by formulation and environmental factors. The HRIP system demonstrated sensitivity to changes in spray angle and can quantify drug deposition as a function of geometry, flow rate, and other experimental factors.