Background/Objectives: Carrier-based dry powder inhaler (DPI) formulations remain the predominant platform for respiratory drug delivery. However, integrated development frameworks that align upstream particle engineering with downstream manufacturing are underdeveloped. This study aimed to develop a comprehensive Quality-by-Design (QbD) strategy that systematically connects jet milling, formulation design, and blending scale-up for carrier-based DPI products containing micronized crystalline active pharmaceutical ingredient (API). Methods: Phenytoin was selected as a model API to investigate process–formulation–performance relationships. Jet milling parameters were optimized to generate three distinct API particle size distributions while monitoring solid-state integrity. A design of experiments (DoE) evaluated the impact of API particle size and lactose fines level on aerodynamic performance (fine particle fraction, FPF) and powder processability (flowability, compressibility). High-shear and low-shear blending techniques were compared, and a novel V-shell blending scale-up methodology was developed based on maintaining particle fall velocity and total strain across multiple scales (one-, two-, and eight-quart). Results: Optimized jet milling produced inhalation grade API particles with controlled amorphous content localized to high-energy processes. DoE analysis identified a design space in which API Dv90 of 2.9–4.5 µm and coarse lactose <96% maximized both aerosolization and blend flowability. Low-shear blending achieved superior lung delivery (FPF 62.6 ± 1.7%) compared with high-shear micing (50.1 ± 1.5%). The particle-velocity-based scale up strategy produced statistically equivalent FPF and ED across all scales (p < 0.01), with content uniformity (RSD ≤ 5%) and variability comparable to commercial DPIs. Conclusions: This integrated QbD framework demonstrates that the co-optimization of particle size engineering, formulation composition, and blending dynamics is essential for achieving robust and scalable DPI products. The approach offers a material-sparing, efficient pathway from API characterization through commercial scale manufacturing and is broadly applicable to respiratory drug development.
Amorim et al. (Sun,) studied this question.