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16 August 2024 Inhalation internal morphology of microparticles produced by solution BDP pMDIs formulated with ethanol in HFA-134a and HFA-227a. e particles generated were evaluated for their morphology by SEM and solid phase by Raman microscopy. Despite remain- ing predominantly amorphous in all tested condi- tions, drug particles produced during actuations in dry air exhibited a solid, spherical morphology, while those produced in high humidity were highly porous. Resultant particles could ultimately affect particle density and wettability, with potential implications for pharmacokinetic profiles. e study suggests that condensed water vapor or ice deposition from ambient humidity acts as a templating agent during particle formation from propellant evaporation. Ear- lier descriptions highlighted how the morphology of particles could influence the dissolution of emitted aerosol particles. Consequently, these studies offer insights into the potential impact of humidity on dissolution in the respiratory tract. Other factors It is essential to recognize that solution-based pMDIs exhibit distinct behavior compared to suspen- sion-based formulations. In suspension systems, the minimum output size of a droplet is largely deter- mined by the size of the suspended particles within the atomized droplets. In contrast, in solution-based pMDIs, the size of emitted droplets is primarily influ- enced by factors such as the design of the actuator and the composition of the formulation. erefore, it is important to note the distinct drug release behav- ior exhibited by solution-based pMDIs compared to suspension-based formulations. Arora, et al. showed that the solution QVAR pMDI with BDP exhibited significantly faster and greater dissolution and per- meation than the suspension Vanceril ® pMDI with BDP (Schering-Plough, Kenilworth, New Jersey, US) over 10 hours [13]. Conclusions At present, there are no established regulatory man- dates or standardized procedures for conducting in vitro dissolution testing of pMDI products. ere- fore, it is imperative to select or develop a dissolution testing methodology that is tailored to the specific attributes of the pMDI formulation. is article outlines the factors that could influence in vitro dissolution of pMDI aerosols, offering guid- ance for optimizing formulation design by selecting appropriate APIs and excipients, as well as enhancing the manufacturing process. Furthermore, the arti- cle suggests directions for developing robust disso- lution technologies to assess batch consistency, such as selecting a suitable dissolution medium and con- sidering the impact of humidity and temperature during experimentation. To evaluate the extent of the differences among the various dissolution media, a study used fluticasone propionate and beclomethasone dipropionate to represent inhaled drugs with poor aqueous solubil- ity, which may be dissolution-limited, resulting in relatively slow dissolution profiles. For FP from the Flixotide ® 50 μg pMDI (GSK, Brentford, UK), it was observed that the dissolution rate in SLF (~2%) was higher than in Gamble's solution (~1%), but lower than in 0.5% SDS (~9%) over 30 minutes. Similarly, BDP from QVAR 50 μg pMDI exhib- ited a similar trend across these three media, with 0.5% SDS showing the highest dissolution (~30%), followed by SLF (~25%) and Gamble's solution (~15%). Additionally, the same formulations of BDP studied by Arora, et al. using the Transwell dis- solution method demonstrated a dissolution rate of approximately 3% in water as a dissolution medium at the 30-minute time point. Temperature and humidity Environmental conditions, such as temperature and humidity, at which the aerosolization and/or dissolu- tion study takes place could also impact the dissolu- tion rates of aerosol particles generated from pMDIs. Previous work [23] has indicated that salbutamol sulfate transitions from a crystalline solid to a satu- rated solution at approximately 92% relative humid- ity (RH). is is a result of temperature altering the RH level and substantially impacting the saturation vapor pressure of air, consequently influencing the kinetics of drug dissolution. In a recent study [24], electrodynamic balance (EDB)—a single particle measuring technique— was utilized to collect information on the matura- tion kinetics of drug/excipient droplets and provide unique insights about how non-volatile excipients and humidity influence particle conformation during maturation. pMDIs were systematically formulated to vary glycerol and isopropyl myristate (IPM) con- centrations, with ethanol as a cosolvent, to determine the effect of humidity on BDP particle development and wetting. BDP particle morphologies were com- pared among aerosols generated from pMDIs con- taining different ratios of BDP/ethanol:glycerol or BDP/ethanol:isopropyl myristate at various relative humidity levels, ranging from dry air (0% RH) to 85% RH. Observations revealed that ethanol loss was followed by evaporation of condensed water from the surrounding humidity to generate spherical particles with solid inclusions or compact, irregularly shaped solid particles at 45% RH, depending on the pres- ence or absence of glycerol. However, at RH levels exceeding 95%, condensed water did not evaporate, leading to the formation of solid inclusions of BDP in water/glycerol or water droplets [24]. Another study by Ivey, et al. [25] also showed that environmental humidity affects the surface and