Physical stability of salbutamol amorphous solid dispersion tablets measured by terahertz spectroscopy

The physical stability of salbutamol amorphous solid dispersion (ASD) pharmaceutical tablets, manufactured via a novel strategy employing liquid drug feeding during hot-melt extrusion, was evaluated using terahertz time-domain spectroscopy (THz-TDS). A total of 41 salbutamol ASD pharmaceutical tablets were individually tracked for longitudinal assessment, and physical stability was demonstrated over 15 months with no detectable salbutamol crystals. The absorption coefficient spectra retained smooth, continuously increasing profiles, which match the vibrational density of states of amorphous solids. The absence of the crystalline salbutamol phonon mode at 0.98THz was substantiated by first- and second-derivative spectral analyses. Temporal consistency in both absorption coefficient and refractive index spectra across all tablets further supported the lack of detectable crystallinity. These observations were equally demonstrated by the simpler, more straightforward and physically interpretable absorption coefficient ratio α_0.98THz/α_0.75THz of the salbutamol peak to the baseline. It was found that α_0.98THz/α_0.75THz is consistent over time and agrees with that of the salbutamol ASDs, whilst distinctively differentiating the pharmaceutical tablets from crystalline salbutamol. The direct, rapid, and non-destructive assessment of crystallinity, particularly via the simple, physically interpretable absorption coefficient ratio, makes THz-TDS advantageous for longitudinal stability studies and individual tracking of solid dosage forms during drug product development.