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Inhalation August 2024 11 ing through aqueous pores within the intercellular tight junctions. Ionized molecules, which are typi- cally water-soluble, exhibit reduced absorption rates due to interactions with the lipids and proteins envel- oping these aqueous pores. Moreover, absorption rates may further decrease with an elevated molecular weight of the drug [11]. As for drugs that are poorly soluble or administered in high doses via pMDIs, the dissolution process may be the limiting factor for absorption. To investigate respirable aerosols of seven pMDI inhaler products with varying API solubility, Sakagami, et al. [12] uti- lized a Transwell method. is approach involved exposing the aerosols to 10 ml of simulated lung lin- ing fluid (SLF) at 37 °C and approximately 100% relative humidity. e findings indicated that three APIs with high-to-intermediate solubility (flunisolide (FN), triamcinolone acetonide (TA) and budesonide (BD)) exhibited first-order "sink" behavior, achiev- ing complete dissolution within 6 hours. Conversely, for pMDIs formulated with poorly aqueous-soluble APIs (fluticasone propionate (FP), beclomethasone dipropionate (BDP), mometasone furoate (MF) and ciclesonide (CIC)), the dissolution profiles showed kinetically pseudo zero-order kinetics. For these pro- files, at 9 hours, 50% or less of the APIs had been transferred, indicating that the slow dissolution is due to the volume of the SLF and unable to reach the "sink" condition in 10 ml of the donor fluid. Addi- Factors influencing dissolution rates of pMDIs e dissolution rate of the maturated particles pro- duced from a pMDI is influenced by various factors, including the physicochemical properties of the API itself (such as intrinsic solubility), as well as the mor- phology, particle size and solid-state properties of the emitted particles. Additionally, the formulation's excipients, including the concentration and types of volatile excipients, the presence of non-volatile liquid excipients, and the addition of a second drug, can impact dissolution. Other variables such as dissolu- tion media, temperature and humidity also play cru- cial roles in determining the dissolution rate of the aerosols generated from pMDIs. API intrinsic solubility Major factors that could impact the dissolution of the generated pMDI aerosols are the physicochem- ical properties of the formulation and the intrinsic solubility of APIs in the epithelial lining fluid or sol- vent systems. However, aqueous solubility of a drug does not consistently affect the pharmacokinetic profiles of inhaled particles, as the properties of the API can also impact drug permeability across the lung epithelium. Hydrophilic drugs tend to be absorbed from the lungs more slowly than lipophilic drugs, likely pass- Figure 1 Processes involved in the inhalation of pMDI aerosols: 1) Atomization to form droplets from the pressurized metered dose inhaler, 2) aerosol maturation to form particles of different size and morphologies, 3) deposition of particles in the various regions of the airways, 4) dissolution of particles in the airway surface liquid and 5) permeability of drugs across the airway epithelium. (Created with BioRender.com.) Systemic Circulation 1 2 3 4 5