Impact of formulation variables on the quality attributes of psilocybin-loaded oral thin films for early-phase development

Psilocybin is an emerging investigational compound with therapeutic potential in neuropsychiatric disorders, creating a need for flexible and scalable dosage forms suitable for early clinical development. This study aimed to develop and evaluate psilocybin-loaded oral thin film (OTF) formulations as a dose-proportional platform for early-phase clinical use. OTFs were prepared using a solvent casting process and characterized with respect to physicochemical properties, drug loading, content uniformity, disintegration, dissolution behavior, and short-term stability. Psilocybin was fully solubilized in the aqueous phase and successfully incorporated into the polymeric film matrix. All formulations disintegrated and dissolved within 180 s. Drug loading ranged from 6.73% to 24.07%, with recovery between 89.78% and 99.56%. The maximum amorphous psilocybin loading without detectable crystallinity was 11.75%. Stability studies conducted at 25 ± 2 °C / 60 ± 5% RH and 40 ± 2 °C / 75 ± 5% RH over three months demonstrated no significant changes in film appearance or drug content. A psilocybin-loaded oral thin film formulation with acceptable short-term physical and chemical stability was successfully developed, supporting its suitability for early-phase pharmaceutical development. Owing to their inherent dose proportionality based on film size, OTFs enable flexible dose adjustment and broad dose exploration within a single bracketed stability program, supporting efficient formulation development for early-phase clinical trials.