Comprehensive Aerodynamic and Physicochemical Stability Evaluations of Nanocrystal-Based Dry Powder Inhalers: The Role of Mannitol and Leucine in Enhancing Performance.

: Nanocrystals, a carrier-free nanotechnology, offer significant advantages for pulmonary drug delivery by enhancing the dissolution and solubility of poorly soluble drugs while maintaining favorable biological properties and low toxicity. This study aims to investigate the aerodynamic performance and stability of nanocrystal-based dry powders (NC-DPs). : Nanocrystalline suspensions were produced via wet media milling and subjected to stability studies before undergoing nano spray drying. A factorial design was employed to optimize the process parameters. The influence of mannitol and leucine, individually and in combination, was evaluated in terms of aerodynamic properties (Aerodynamic Particle Sizer (APS), in silico modeling) and the physicochemical stability at room temperature (in a desiccator) and accelerated conditions (40 ± 2 °C, 75 ± 5% relative humidity). : APS analysis revealed that leucine-containing powders (K-NC-Ls) exhibited the smallest median (1.357 µm) and geometric mean (1.335 µm) particle sizes, enhancing dispersibility. However, in silico results indicated the highest exhaled fraction for K-NC-L, highlighting the need for optimized excipient selection. Although mannitol showed the lowest exhaled fraction, it was mainly deposited in the extra-thoracic region in silico. The mannitol/leucine combination (K-NC-ML) revealed a low exhaled fraction and high lung deposition in silico. Also, K-NC-ML demonstrated superior stability, with a 6% reduction in D[0.5] and a 5% decrease in span overtime. Furthermore, no significant changes in crystallinity, thermal behavior, drug release, or mass median aerodynamic diameter were observed under stress conditions. : These findings confirm that combined incorporation of mannitol and leucine in NC-DP formulations enhances stability and aerodynamic performance, making it a promising approach for pulmonary drug delivery.