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Introduction: Carrier-free formulations utilized in DPIs are preferred in pulmonary drug delivery systems due to their capacity to carry higher doses of API, adjust particle size for enhanced lung deposition, and provide stability of the formulation. Spray-drying as a one-step, scalable and straightforward drying technique is highly promising for production of inhalable carrier-free powder formulations. Trehalose, a non-reducing disaccharide, stabilizes biologics during the spray-drying process against heat and dehydration, preserving protein integrity and bioactivity. It may enable long-term storage of APIs, often together with other excipients to prevent aggregation. Pullulan combined with trehalose shows promise in humidity and temperature stabilization, as well as in enhancing aerosol performance. However, the cohesive nature of the trehalose-pullulan powder formulations can lead to issues regarding dispersibility and agglomeration, which can be mitigated by adding L-leucine.

Aim: To investigate a carrier-free DPI platform for pulmonary delivery of sensitive small molecule or biological APIs and investigate the effects of composition of excipients, their concentrations in feed solution and spray drying process parameters on the particles and powder properties.

Method: Various compositions of the three excipients of trehalose, L-leucine, and pullulan, along with different spray-drying process parameters and solution concentrations, were used to prepare powder formulations. The powder formulations were characterized in terms of particle size and distribution, morphology, degree of crystallinity, thermal properties, flowability and RMC.

Results: The morphological analysis of powder particles indicates that L-leucine, constituting almost 17% of the mass fraction, enriches at the particle surface while maintaining the corrugation achieved by pullulan. Thermal and solid-state analysis showed good protection of particles against environmental moisture in the presence of L-leucine. By applying suitable spray-drying process parameters, particles with promising characteristics in terms of particle size were obtained. The prepared formulations showed enhanced manufacturability properties.