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[Display omitted] • Gelatin was used to develop a swellable matrix system for inhalable dry powder formulations to increase lung retention and control the release of drugs through ionic interactions. • A Box-Behnken approach was used to optimize aerodynamic performance by testing different combinations of SD process parameters. • Cromoglicate sodium (CS) and ipratropium bromide (IBr) microspheres were highly dispersible with a respirable fraction near 50% and a fine particle fraction near 60% • Only uncrosslinked CS and IBr microspheres increased their size by swelling after 5 min (ten and four times, respectively), which could allow for increased lung retention. • The formulations are produced with an accessible manufacturing process, a safe excipient that enhances particle dispersion, and has the potential to control the release of the drugs by a matrix-based approach. Controlled-release formulations for pulmonary delivery are highly desirable for treating chronic diseases such as COPD. However, a limited number of polymers are currently approved for inhalation. The study presents a promising strategy using gelatin as a matrix for inhalable dry powders, allowing the controlled release of ionic drugs. Ionized cromoglicate sodium (CS) and ipratropium bromide (IBr) interacted in solution with charged gelatin before spray drying (SD). Calcium carbonate was used as a crosslinker. The microspheres showed remarkable aerosol performance after optimizing the SD parameters and did not cause cytotoxicity in A549 cells. The microspheres were highly dispersible with ∼ 50–60% of respirable fraction and fine particle fraction 55–70%. Uncrosslinked microspheres increased their size from four to ten times by swelling after 5 min showing potential as a strategy to avoid macrophage clearance and prolong the therapeutic effect of the drug. Crosslinkers prevented particle swelling. Ionic interaction generated a moderate reduction of the drug release. Overall, this study provides a novel approach for developing DPI formulations for treating chronic respiratory diseases using a biopolymer approved by the FDA, potentially enhancing drug activity through controlled release and avoiding macrophage clearance. [ABSTRACT FROM AUTHOR]