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Recently, there has been a surge in interest surrounding the development of carrier-free dry powder formulations intended for pulmonary drug delivery. This may be attributed to the multiple advantages offered by these formulations in contrast to conventional carrier-based…. 24 February 2024 Inhalation Shell formers in the formulation design of spray-dried particles Using dispersible carrier-free dry powder formulations to advance pulmonary drug delivery Mani Ordoubadi, PhD University of Alberta Introduction Recently, there has been a surge in interest surround- ing the development of carrier-free dry powder for- mulations intended for pulmonary drug delivery. is may be attributed to the multiple advantages offered by these formulations in contrast to conven- tional carrier-based products. ese benefits include precise dosing, enhanced drug delivery efficiency, absence of carrier-drug interactions and the potential for more potent formulations. Spray drying is the preferred technique for the pro- duction of carrier-free dry powder formulations, owing to its continuous and scalable nature. rough particle engineering, it is possible to design complex particles with accurate control over particle size. Additionally, spray drying can generate amorphous formulations, which can provide improved bioavail- ability for hydrophobic drugs and is the desired solid phase for biologics [1]. On the other hand, spray- dried powders are generally cohesive due to their typ- ically amorphous state, making them susceptible to moisture uptake, which can negatively affect product efficacy and stability. Shell forming excipients can play a pivotal role in overcoming challenges related to particle cohesion, hygroscopicity and overall stability. Due to their unique physico-chemical properties, this class of excipients can form a protective layer on the surface of the droplet during drying, resulting in core-shell structured particles. By strategically incorporat- ing shell formers into spray-dried products, formu- lators can enhance dispersibility and mitigate the potential drawbacks associated with cohesive pow- ders. is article delves into the multifaceted role of shell formers, shedding light on their mechanisms of action, impact on particle properties and a practical methodology for their formulation design. Mechanisms of shell formation To facilitate effective shell formation during the dry- ing process, the excipients must possess specific attri- butes that enable efficient surface enrichment. is surface enrichment occurs through two primary mechanisms during the drying of droplets: surface accumulation driven by a high Péclet number and surface adsorption owing to the excipients' surface activity (Figure 1). e enhancement in aerosol per- formance results from the diminished interparticle contact area attributed to the wrinkled morphology Figure 1 Main mechanisms of shell formation. Scanning electron micrographs (SEM) of trehalose/pullulan particles, reproduced from reference 2 with permission. Trehalose Strong Surface Activity High Péclet Number Trehalose + Pullulan Trehalose + Trileucine