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Inhalation February 2024 27 tigation, it was discovered that the combined glass formation of trileucine and pullulan resulted in reduced processing losses for a spray-dried anti- campylobacter bacteriophage formulation. is effect was likely attributed to the glass stabilization properties exhibited by these shell formers [18]. In contrast, other investigations have indicated that incorporating a crystalline leucine shell encasing a glassy core provides improvement in terms of safe- guarding against moisture absorption and subse- quent destabilization mechanisms [19, 20]. erefore, the optimal solid state of the shell former can differ based on practical considerations, formula- tion prerequisites and stability requirements. Antici- pating the solidification behavior of each constituent within the formulation is crucial for effective mecha- nistic formulation design, as the critical solidification concentrations depend on the specific solid state of each component. ere are a number of analytical techniques for assessing the solid state of excipients and APIs after spray drying, such as powder X-ray diffraction (PXRD), Raman spectroscopy and differ- ential scanning calorimetry (DSC). Critical concentrations Obtaining an estimation of the concentration at which each solute initiates solidification is pivotal for the effective design of formulations involving shell formers. To simplify, this value can be referred to as the critical concentration. In cases where materials undergo phase separation into an amorphous state, the critical concentra- tion is typically the point at which the viscosity within the droplets exhibits a notable increase pre- venting the further decrease in droplet diameter [21]. Alternatively, in situations where such data is unavailable, it is reasonable to consider the solid density of the material's amorphous state as the critical concentration. For compounds that can undergo nucleation and crystal growth during spray drying, the critical con- centration is a value larger than the solubility of that compound in the solvent environment and smaller than the spontaneous nucleation concentration, which is the concentration at which nucleation is predicted to start instantly [21]. Mechanistic formulation design of core-shell particles Predicting the precise kinetics of shell formation is intricate and highly contingent on the specific case, varying with different combinations of active ingredients and excipients. To establish a universal methodology aiding in the formulation design of compositions containing shell formers, a straight- forward approach involves comparing the instances to reach the critical concentration and surface sat- uration of these excipients with those of other con- design phase, this timescale can be compared against critical solidification points of other compounds to ensure efficient shell formation properties. For example, an aqueous droplet containing 1 mg/mL of trileucine would reach monolayer saturation in about 1.6 ms. Following the establishment of a saturated mono- layer, the surface-active shell former will inevitably undergo a form of solidification—either crystalliza- tion or amorphous phase separation. Both processes are anticipated to initiate on the surface, facilitated by the presence of the monolayer and the surface enrichment attributable to surface recession. As the drying process continues, the remaining excip- ients and active components within the droplets solidify, ultimately yielding the desired core-shell structure. is hypothesized mechanism of shell formation for surface-active excipients is depicted schematically in Figure 4. Lecithin, tween, some phosphatidylcholines (such as DPPC and DSPC) and hydrophobic peptides (such as leucine, trileu- cine and isoleucine) are examples of surface-active shell formers. Solid phase considerations Depending on their physico-chemical character- istics, shell formers can exist in crystalline, amor- phous or hybrid states. e selection among these states is contingent upon formulation necessities, the inherent physical properties of the active com- ponents and the presence of additional excipients. One solid state might offer advantages over another based on specific requirements. For instance, prior research demonstrated that the crystallization of leucine during the spray drying of a formulation containing an adjuvanted tuberculosis vaccine can- didate in an aqueous emulsion format had adverse effects on the emulsion size following reconstitu- tion of the solid powders [17]. In a separate inves- Figure 4 Mechanism of shell formation of a surface-active excipient. Surface adsorption starts Saturated monolayer formed at t Γ max Solidification starts Shell formation Dried particle