Detecting absence of crystallinity in solid dosage forms with at-line terahertz process analytical technology

Amorphous solid dispersions (ASDs) enhance the solubility and bioavailability of drugs, yet their inherent instability and the risk of recrystallisation make the absence of crystallinity a critical quality attribute. Despite developments in non-destructive spectroscopic process analytical technologies (PAT), their applications to final amorphous dosage forms are relatively limited. This study establishes non-destructive terahertz time-domain spectroscopy (THz-TDS) as a simple, rapid and robust at-line PAT for determining the absence of crystallinity in solid dosage forms. Two independent and physically interpretable approaches are established: (i) absence of characteristic phonon absorption peaks, and (ii) the ratio of absorption coefficients at a crystalline phonon frequency to a low-noise baseline frequency, which accounts for the vibrational density of states characteristic of disorder. Both simple methods unambiguously determined the absence of crystallinity in salbutamol ASD tablets, the model system used for evaluation. The methods are robust to scattering and excipient absorption, and are validated across multiple instruments and over long-term storage. These findings substantiate THz-TDS as a practical at-line PAT for amorphous solid dosages and as a feasible strategy for real-time release testing, as well as further extending its utility as a multi-attribute PAT. The potential of at-line THz-TDS PAT in predicting dissolution time of amorphous solid dosages shall be explored in future.