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Pressurized metered dose inhalers (pMDIs) have become a popular dosage form for pulmonary drug administration due to their portability, convenience, accurate dosing and cost-effectiveness. They deliver the active pharmaceutical ingredient (API) along with excipients (such as ethanol and propellant) onto the lung surface in a solid or semi-solid form. 10 August 2024 Inhalation Factors influencing the in vitro dissolution rates of pMDI aerosols Considerations for optimizing formulation design and manufacturing Lin Zhang, PhD a ; William Glover, PhD a ; David A. Lewis, PhD b ; Robert D. Johnson, BSc b ; Daniel I. Lewis b ; Paul M. Young, PhD a and Hui Xin Ong, PhD a, c a Ab Initio Pharma b Oz-UK Limited c Macquarie University Introduction Pressurized metered dose inhalers (pMDIs) have become a popular dosage form for pulmonary drug administration due to their portability, convenience, accurate dosing and cost-effectiveness. ey deliver the active pharmaceutical ingredient (API) along with excipients (such as ethanol and propellant) onto the lung surface in a solid or semi-solid form. e primary fluid found in the central conducting regions of the lungs is the mucus layer, which coats the apical surface of epithelial cells. Within healthy individuals, the upper airways typically hold a vis- cous fluid layer that ranges from approximately 10 to 30 mL. is layer is predominantly composed of 95% water, with the remaining 5% comprising a mixture of inorganic salts, mucin, proteins and lipids. e systemic absorption and bioavailability of the inhaled APIs are governed by the dissolution process of the deposited aerosol particles in the lim- ited lung lining fluid and the permeability of the drug across the epithelial cells [1]. Employing in vitro dissolution studies of pMDIs is therefore crucial for assessing the release of drugs from pMDIs and their subsequent availability for systemic absorption. e utilization of in vitro dissolution systems yields valuable data for deci- sion-making, enabling the prediction of drug phar- macokinetics (PK) during the initial phases of drug development and optimization. is data facilitates more precise forecasts of in vivo drug behavior, thereby helping to avoid expensive failures in the late stages of development. Conventional dissolution testing techniques, like the United States Pharmacopoeia (USP) apparatus 1 and 2, are typically employed to simulate the gas- trointestinal (GI) tract when evaluating solid oral dosage forms such as capsules and tablets. How- ever, alternative methods have emerged to assess the in vitro drug dissolution characteristics of micro- particles deposited from oral inhalation pMDIs. ese methodologies include the USP Apparatus 2 paddle method, the modified USP apparatus 4 flow-through system, a diffusion model based on a transdermal diffusion Franz cell and the Transwell ™ System, Corning, Corning, New York, US [2, 3]. As shown in Table 1, the microparticles to be evaluated can be deposited on certain membranes or inserts (Snapwell™ Inserts, Corning, Corning, New York, US) or microscope glass coverslips using the Twin Stage Impinger (TSI, Copley Scientific, Notting- ham, UK), Andersen Cascade Impactor (ACI, Cop- ley Scientific), Next Generation Impactor (NGI, Copley Scientific) or the DissolvIt ® System (Inha- lation Sciences, Huddinge, Sweden). e dissolution rate of a substance refers to the speed at which it dissolves in a solvent system to form a solution. is process is governed by the affinity between the solid substance and the solvent, as well as factors related to the crystal packing of the solid. e physicochemical properties of a dissolved API play a significant role in particle formation during the maturation of emitted aerosol particles after a pMDI is actuated on the epithelial cell surface or sol- vent system. is article aims to provide a thorough overview of the factors that affect in vitro dissolution rates of maturated pMDI aerosols (Figure 1).