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Inhalation February 2024 25 Surface-active excipients find application in the spray drying of inhalable pharmaceutical microparticles to augment production yield and aerosolization char- acteristics, mitigate water uptake in the resultant powder and safeguard against protein denaturation, among other benefits [7-9]. Remarkably, even min- ute quantities (as little as 1% w/w of solids loading) of surface-active materials within the feed solution can exert discernible impacts on the surface mor- phology of spray-dried particles [10]. Under equilibrium conditions, the surface activity of an excipient is quantified through the maximum sur- face excess, Γ max , and the maximum surface pressure, π max . e surface excess is defined as the difference between the number of solute moles on the surface and those on an imaginary plane within the solution, per unit area. In dilute solutions, surface excess is often assumed to be equal to the surface adsorption per unit area, with negligible deviation. Surface pres- sure, meanwhile, characterizes the reduction in sur- face tension upon the introduction of surface-active agents to the solvent. e surface rheology of atomized droplets contain- ing surface-active excipients has been demonstrated to exert substantial influence over the control of the dried particles' surface morphology [10]. Surface rhe- ology, often characterized by the dilatational mod- ulus, as shown below, defines the elasticity of the adsorbed surfactant film [11, 12]. ϵ= dσ dlnA A solution droplet with a high surface dilatational modulus will effectively withstand shrinkage during the evaporation process, thereby yielding a particle with a wrinkled and dented surface. Conversely, a droplet featuring a lower dilatational modulus will maintain its smooth surface throughout evapora- tion, resulting in the formation of a smooth solid or the reduction in surface energy of the dried parti- cles. ese factors can collectively lead to a reduction in interparticle cohesion. High Péclet number surface enrichment Within the spray-drying literature, the Péclet num- ber serves as a tool for assessing the relative signif- icance of time scales related to the rate of droplet surface area reduction caused by evaporation and the Fickian diffusion extending from the droplet surface to its interior [3]. Mathematically, the Péclet number of component i is expressed as follows: Pe i = κ 8D i Here, κ denotes the droplet's evaporation rate, while D i represents the diffusion coefficient of the specific component within the droplet. Notably, the equa- tion underscores that compounds characterized by a larger molecular size and, consequently, a smaller dif- fusivity, will yield a relatively elevated Péclet number, resulting in higher surface enrichment. Cyclodextrins and some polysaccharides such as inu- lin, pullulan and starches are materials often seen in spray drying that have a strong probability of form- ing shells due to their high Péclet numbers. It is important to note that shell formers can also benefit from a high Péclet number due to early precipitation and the subsequent crystal growth or phase separation. In this context, the growing solid domains exhibit an increasing Péclet number, leading to surface accumulation. Consequently, for such materials, it is advisable to restrict the appli- cation of surface enrichment equations based on molecular diffusivity [4] only until the projected point of precipitation and growth [5]. Leucine serves as an example of an excipient where the formation of the shell is thought to result from a combination of its surface activity and its ability to quickly initiate nucleation and crystal growth due to its low aqueous solubility. ese mechanisms of shell formation due to high Péclet numbers are shown schematically in Figure 2. Surface activity Another attribute that qualifies an excipient as an effective shell former is its surface activity. Surfac- tants, also known as surface-active agents, encom- pass a wide range of materials that adsorb at the interface between two phases. e presence of sur- factant molecules on the interface typically leads to a reduction in the surface tension of aqueous solu- tions. is reduction occurs due to the surfactant molecule's affinity for both air and water, a property known as amphiphilicity [6]. Figure 2 Mechanisms of shell formation due to a high Péclet number (Pe). Large molecule Large Pe Small molecule Small Pe Low solubility Surface enrichment from the start Early phase separation or crystallization and crystal growth Same Pe Increasing Pe Solidification limit reached on the surface Crystals or separated domains accumulate on the surface