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14 August 2024 Inhalation Motivated by e Kigali Amendment to the Mon- treal Protocol on Substances that Deplete the Ozone Layer, pharmaceutical companies are placing a top priority on replacing high global warming poten- tial (GWP) MDI propellants with low GWP alter- natives. Studies have recently been conducted to investigate whether these propellants affect in vitro dissolution rates, to ensure consistent performance as propellant transitions are made [6]. To conduct a direct comparison with commercially available Clenil 100 MDIs (Chiesi) containing HFA-134a, we man- ufactured MDIs (Oz-UK Ltd, Chippenham, UK) containing low GWP propellants (HFO-1234ze(E) manufactured by Honeywell, (Charlotte, North Car- olina, US) and HFA-152a manufactured by Koura (Waltham, Massachusetts, US) using existing, off- the-shelf components. ese MDIs were formulated with a standard composition of 100µg/50µl beclo- methasone dipropionate, ethanol and glycerol, and utilized standard actuator technology. e dissolution of BDP particles from each of the three MDI formu- lations (containing HFA-134a, HFO-1234ze(E) or HFA-152a) was assessed using a custom, 3D-printed plate equipped with three Snapwell inserts to replace stage 4 of the Next Generation Impactor [18]. Figure 3 shows the cumulative BDP dissolved over time after deposition. It was observed that pMDIs formulated with HFA-134a exhibited faster drug dissolution (T 1/2 = 78 ± 9 mins) compared to BDP particles produced by pMDIs reformulated with HFO-1234ze(E) (T 1/2 = 114 ± 22 mins) and HFA- 152a (T 1/2 = 151 ± 15 mins). Interestingly, these find- ings align with the dissolution rate ranking observed in a previous study for non-glycerol-containing BDP MDIs, suggesting that the influence of the propellant on BDP dissolution persists regardless of the pres- ence of glycerol or ethanol [5]. When a non-volatile component, such as glycerol or polyethylene glycol, is introduced to match the vol- umetric contribution of the formulation and mimic the aerosol properties of the original products, the performance of the formulation is largely dependent on the concentration of non-volatile components present in the formulation [19, 20]. Glycerol alters the particle microphysics of aerosols from solution pMDIs by increasing particle size and modifying the morphology and solid-state of aerosol particles. In a study, it was observed that BDP dissolution decreased compared to formulations without glyc- erol. is was attributed to the higher solubility of glycerol compared to BDP, leading to competition for solvent uptake and consequently slowing the BDP dissolution rate [14]. Similarly, in another study of BDP pMDI formu- lation, the inclusion of glycerol (50% w/w) in the final particles notably reduced the dissolution of BDP. e glycerol-containing particles exhibited a significantly lower dissolution rate (7.8% ± 2.1% Excipients in formulations In the development of inhalation products, additional excipients like cosolvents or adjuvants are frequently incorporated into the formulation. ese added sub- stances can influence the dissolution characteristics of the aerosol spray within the lungs, thereby influ- encing the pharmacological response [17]. For pMDI formulations, the dynamics and mor- phology of emitted pMDI particles can be influ- enced by the composition of the solution. erefore, in solution-based pMDIs, factors such as the concen- tration of co-solvents (e.g., ethanol), the inclusion of non-volatile additives (e.g., glycerol) and the utili- zation of different propellants (such as HFA-134a, HFA-152a, HFO-1234ze(E), etc.) will impact the formation process of droplets. e combinations of these factors will drive the resultant evaporation rate of the propellent mixture and resultant maturation of the particles, which ultimately have a significant effect on the dissolution rate of the emitted particles. A study by Buttini, et al. observed that the dissolu- tion rate of BDP decreased from 86% to 63% over 120 minutes with increasing ethanol percentage in a 12% (w/w) ethanol formulation (BDP Extra- fine) compared to an 8% (w/w) ethanol formulation (Clenil ® , Chiesi) [14]. From transmission electron microscopy (TEM) images of the deposited parti- cles, it was noted that the low ethanol concentration (8% w/w) resulted in a higher percentage of irregu- larly shaped particles (40%) compared to the 12% w/w ethanol formulation, which exhibited irregu- lar surfaces in 25% of the particles. is observa- tion suggests that the irregular surface of the formed particles may have larger surface areas, consequently enhancing dissolution. Figure 3 The dissolution of BDP particles on stage 4 of the modified NGI assessed over 180 minutes (n = 3). Average cumulative drug release percentage dissolution profiles are presented with standard deviations. 0 20 40 60 80 100 120 140 160 180 Time (minutes) 70 60 50 40 30 20 10 0 Cumulative Drug Dissolved (%) Clenil ® HFO-1234ze(E) HFA-152a