Analysis of Local Free Volume and Hydration in Pharmaceutical Polymer Films Using Positron Annihilation Lifetime Spectroscopy

The relationship between the nanoscale free volume of pharmaceutical polymer films and their hydration behavior remains poorly understood. Eight pharmaceutical polymers were screened at three concentration levels within a quality-by-design framework; only two poly(vinyl alcohol) grades (PVA EG-30P and EG-40P), hydroxypropyl cellulose (HPC), and sodium alginate (Na-alginate) formed continuous films. These were characterized by positron annihilation lifetime spectroscopy (PALS), loss on drying (LOD), and swelling analysis. PALS clearly differentiated HPC, Na-alginate, and PVA, whereas the two PVA grades were similar and the concentration had only a minor effect. HPC showed the largest free volume holes (86.7–89.5 Å3), and Na-alginate the smallest holes (36.9–39.6 Å3) together with the highest LOD (20.2–21.6%). Across the 12 polymer–concentration combinations, the free volume hole volume correlated inversely with LOD (Spearman ρ = −0.85) but not with the equilibrium swelling index, as both HPC and Na-alginate swelled considerably more than PVA. Thus, PALS discriminates film-forming pharmaceutical polymers and reflects their residual water content, but the free volume of the air-dried films does not predict their swelling capacity.