  Near infrared (NIR) and Raman spectroscopy combined with multivariate
analysis are established techniques for the identification and quantification
of chemical properties of pharmaceutical tablets like the concentration of
active pharmaceutical ingredients (API). However, these techniques suffer from
a high sensitivity to particle size variations and are not ideal for the
characterization of physical properties of tablets such as tablet density. In
this work, we have explored the feasibility of terahertz frequency-domain
spectroscopy, with the advantage of low scattering effects, combined with
multivariate analysis to quantify API concentration and tablet density. We
studied 33 tablets, consisting of Ibuprofen, Mannitol, and a lubricant with API
concentration and filler particle size as the design factors. The terahertz
signal was measured in transmission mode across the frequency range 750 GHz to
1.5 THz using a vector network analyzer, frequency extenders, horn antennas,
and four off-axis parabolic mirrors. The attenuation spectral data were
pre-processed and orthogonal partial least square (OPLS) regression was applied
to the spectral data to obtain quantitative prediction models for API
concentration and tablet density. The performance of the models was assessed
using test sets. While a fair model was obtained for API concentration, a
high-quality model was demonstrated for tablet density. The coefficient of
determination for the calibration set was 0.97 for tablet density and 0.98 for
API concentration, while the relative prediction errors for the test set were
0.7% and 6%for tablet density and API concentration models, respectively.
