Respiratory drug delivery: physiological, technical, and regulatory considerations for dissolution testing of orally inhaled dry powder aerosols.

INTRODUCTION: Pharmaceutical development of dry‑powder inhaler (DPI) products has traditionally relied on aerodynamic performance metrics. However, these parameters do not capture the post-deposition fate of inhaled particles, where dissolution impacts mucociliary clearance, macrophage uptake, retention, and systemic absorption, particularly for poorly soluble drugs. Consequently, there is increasing interest in understanding the dissolution behavior of orally inhaled drug products.

AREAS COVERED: This review critically examines the unique physiological environment of the lungs and the interactions of inhaled drugs with surfactants and mucins, highlighting why the respiratory tract cannot be regarded as a miniaturized gastrointestinal tract. It also discusses the dynamic interplay between dissolution and pulmonary clearance, alongside key methodological challenges in dissolution testing, including sample collection, apparatus design, dissolution media, and data analysis. Literature published between 1968 and 2026 was identified through searches of PubMed, Scopus, Google Scholar, and Web of Science databases.

EXPERT OPINION: Widespread implementation of dissolution testing is hindered by the lack of standardized methodologies on aerosol collection, dissolution apparatuses, hydrodynamic conditions, and physiologically relevant dissolution media that can accurately replicate the lung environment. Future progress will require harmonized regulatory guidance, validated testing platforms for routine quality control, and advanced biorelevant airway models for in vitro-in vivo relationship.