Unveiling surface energetics-wettability relationships in pharmaceutical microparticles: Advanced characterization...

The unpredictable wettability of pharmaceutical microparticles, often stemming from complex phase transitions during processing, frequently eludes conventional unidimensional assessments of surface hydrophilicity. In this study, mannitol-leucine microparticles were fabricated via spray drying and spray freeze drying. Their structural properties-including morphology, particle size, and polymorphism-were systematically correlated with surface energetics (dispersive energy, acid-base characteristics, and hydrophilic site distribution) as delineated by inverse gas chromatography (IGC). Increasing leucine content induced pronounced surface wrinkling, sustained crystalline stability, and resulted in larger particle sizes in spray-dried samples. Conversely, spray-freeze-dried particles maintained a relatively uniform morphology but exhibited unstable δ-mannitol polymorphs with enhanced dispersibility. IGC analysis uncovered that leucine enrichment elevated dispersive surface energy, attenuated surface basicity, and diminished the hydrophilic surface area, with these effects being more pronounced in the spray-dried samples. Crucially, both the absolute hydrophilic surface area and the fractional distribution of hydrophilic domains were identified as key determinants modulating particle wettability and release behavior. This study highlights the capacity of IGC to resolve multiparametric surface energetics, thereby advancing the mechanistic understanding of pharmaceutical particle wettability through non-invasive, high-precision characterization.