Controlling solubility of regenerated silk with additive assisted spray drying

Spray drying is a promising method for producing regenerated silk fibroin powders; however, the drying process often promotes β-sheet formation, which limits powder solubility and affects downstream applications. This study examined the ability of three common excipients-maltodextrin, gum arabic, and trehalose - to influence silk self-assembly during drying, resulting in highly soluble powders. Compared to pure spray-dried silk, which had a solubility of around 67%, adding the excipients improved solubility without changing powder morphology. Maltodextrin and gum arabic increased solubility to 77% and 80%, respectively, but higher levels of these additives caused a slight decrease in solubility. In contrast, trehalose enhanced solubility at all concentrations, reaching nearly complete dissolution (97%) at 40% w/w trehalose. Infrared spectroscopy showed that, while maltodextrin and gum arabic increased β-sheets content beyond their optimal levels, trehalose gradually reduced β-sheets formation across all concentrations. This is likely due to the small size of trehalose, which allows it to form hydrogen bonds with silk protein chains and create a protective hydration shell during drying. To the best of our knowledge, this is the first demonstration that trehalose can suppress β-sheets formation in regenerated silk fibroin during aqueous spray drying. Developing highly soluble silk-trehalose powders offers a potential route to creating a stable storage form of RSF. These powders also have potential in pharmaceutical formulations or as feedstocks for bulk material production through compression moulding or 3D printing.