The process analytical technology (PAT) framework is well established and integral to facilitate process understanding, enable a transition from batch to continuous manufacturing, and improve product quality. Near-infrared (NIR) spectroscopy has been established as a standard PAT tool for many process analytical challenges, including monitoring powder blend homogeneity. However, alternative technologies for monitoring powder blending are of interest due to the importance of the blending step in manufacturing solid oral dosage forms. Terahertz time-domain spectroscopy (THz-TDS) is therefore explored in this study as an alternative tool for monitoring blend homogeneity with the potential for endpoint control in a batch blending process. Powder blends of microcrystalline cellulose (MCC) and dibasic calcium phosphate dihydrate and blends of MCC and granulated α-lactose monohydrate were investigated non-invasively at various compositions using THz-TDS in transmission mode for acquiring spectra from samples enclosed in the blending container. It was found that attenuation- and phase-related parameters acquired with THz-TDS could reliably resolve physical changes related to the homogeneity of the blend. Further evaluations revealed that changes in the bulk density of the blend, in addition to the intrinsic optical properties of the materials, played a critical role in the observed trends for both systems. In contrast, the scattering contribution of the powder was mainly crucial for the attenuation-related parameter in blends with materials of high refractive indices. Finally, THz-TDS measurements were acquired throughout a blending process mimicking a continuous acquisition. The method could follow blending dynamics and resulted in reasonable predictive errors of the content of 0.5 - 2.5 %. Relative standard deviations for high content blends (20 %) were acceptable (3 - 7 %) whereas at low contents (5 %) significantly higher values (9 - 35 %) were found. Based on these findings, THz-TDS is a feasible PAT tool for monitoring blend homogeneity and controlling high content blend processes, although precision and accuracy is considered to improve with a more suitable interface.

γ-aminobutyric (GABA) is the most important inhibitory neurotransmitier in vertebrate central nervous systems. The content level of GABA is related to the different degree of malignancy gliomas. Thus, it can be considered a promising glioma biomarker. In this paper, the spectroscopic properties of GABA have been characterized by combining the THz spectroscopy with low-wavenumber Raman spectroscopy. The experimental results showed that, GABA exhibited three absorption peaks and three refractive index peaks in the range of 0.6-2.1 THz. The limit of detection can reach up to 0.428 % based on the absorption coefficient at the peak of 2.04 THz. Moreover, the low-wavenumber Raman spectrum of GABA showed seven characteristic peaks at 41.0, 50.8, 58.8, 77.2, 98.8, 115.6, 141.2 cm-1 in 0-150 cm-1 region. Moreover, the THz and low-wavenumber theoretical spectra of GABA were simulated with solid-state density function theory, respectively. The calculated results were in good agreement with the experimental observations. On the basis of calculated result, the vibrational motions of each THz and Raman characteristic modes were quantitatively decomposed by analytical mode-decoupling method, where the contribution percentages of external translation, external librations and intramolecular vibration of each vibration modes were analyzed Furthermore, the low-frequency characteristics of GABA was analyzed by combining the THz and low-wavenumber Raman spectroscopy. It is beneficial for the structural information analysis and quantitative identification of biomarker GABA in early stage diagnosis of glioma.

Cell viability assessment is critical, yet existing assessments are not accurate enough. We report a cell viability evaluation method based on the metabolic ability of a single cell. Without culture medium, we measured the absorption of cells to terahertz laser beams, which could target a single cell. The cell viability was assessed with a convolution neural classification network based on cell morphology. We established a cell viability assessment model based on the THz-AS (terahertz-absorption spectrum) results as y = a = (x - b)c, where x is the terahertz absorbance and y is the cell viability, and a, b, and c are the fitting parameters of the model. Under water stress the changes in terahertz absorbance of cells corresponded one-to-one with the apoptosis process, and we propose a cell 0 viability definition as terahertz absorbance remains unchanged based on the cell metabolic mechanism. Compared with typical methods, our method is accurate, label-free, contact-free, and almost interference-free and could help visualize the cell apoptosis process for broad applications including drug screening.

High dilutions of solutions containing extremely small amounts of the initial substance can modify the biological effects of the initial substance molecules. Using terahertz spectroscopy, we studied the possibility of modifying the physicochemical properties of the initial substance by adding high dilutions of high-molecular-weight (IFNγ) and low-molecular-weight (Na2SO4) compounds. In addition, the modifying effect produced by high dilutions of a low-molecular electrolyte (a solution of Na2SO4 salt) on the initial substance was confirmed by conductometry. This method allows measuring electrical conductivity that also depends on the physicochemical properties of the solution, namely, the number of ions and velocity of their movement. Statistically significant differences were shown between terahertz and conductometric characteristics of the initial solution (inorganic salt Na2SO4 or a protein IFNγ) and a solution, where high dilutions of the same substances were added in different concentrations. Interestingly, the differences were more pronounced for the biological molecule. Thus, it has been shown that high dilutions can change the properties of the initial solution; the effect is more pronounced for the protein solution.

In this study, the terahertz (THz) spectra of C3S were obtained in the 0.4-2.3 THz frequency range using different sample preparation methods. In the spectra, a sharp absorption peak of C3S was found at 2.03 THz. Under controlled conditions, the mass ratio of C3S was the most critical factor affecting the strength of the absorption peak, and the absorption coefficient followed the Beer-Lambert law, exhibiting a linear relationship with the mass ratio of C3S. The intrinsic dielectric constants of C3S and polyethylene (PE) were calculated in accordance with the Maxwell-Garnett (MG), Bruggeman (BM), and Landau-Lifshitz-Loovenga (LLL) models, using two-phase composite samples. The results show that the LLL model had the highest accuracy.

In the last decades, Mars has been widely studied with on-site missions and observations, showing a planet that could have hosted life in the past. For this reason, the recent and future space missions on the red planet will search for traces of past and, possibly, present life. As a basis for these missions, Space Agencies, such as the European Space Agency, have conducted many experiments on living organisms, studying their behavior in extraterrestrial conditions, learning to recognize their biosignatures with techniques remotely controllable such as Raman spectroscopy. Among these organisms, the radioresistant cyanobacterium Chroococcidiopsis was irradiated during the STARLIFE campaign with strong radiative insults. In this article we have investigated this cyanobacterium using Raman spectroscopy and extended the characterization of its biosignatures and its response to the radiative stress to the mid- Infrared and Terahertz spectral region using the Fourier Transform InfraRed (FT-IR) and Terahertz Time Domain spectroscopy (THz- TDs), which demonstrates the compatibility and suitability of these techniques for future space missions.

OBJECTIVE: Laryngeal cancer is a common malignancy in otorhinolaryngological head and neck surgery, accounting for approximately one-third of all head and neck malignancies. Terahertz time-domain spectroscopy (THz-TDS) has recently been found to be useful for the detection of tumors. This study was conducted to investigate the application of THz-TDS in the diagnosis of pathological resection margins of laryngeal cancer.
METHODS: Fresh laryngeal cancer tissues from 10 patients with laryngeal cancer were extracted, and after simultaneous HE staining and terahertz imaging, the tumor area, paracancerous area, and normal tissue area of each laryngeal cancer tissue sample were located under a microscope according to the pathological results of HE staining.
RESULTS: The shape contours of the tumor region revealed by terahertz imaging maps and HE staining were similar. In the terahertz spectrum in the frequency range of 0.5-1.9 THz, both the absorption coefficient and refractive index values followed the order tumor > para cancer > normal tissue, with statistically significant differences (P < 0.01). When the terahertz frequency was 1.5 THz, the absorption coefficient of terahertz light waves by laryngeal cancer tissue and the percentage of nuclei showed an extremely high positive correlation (P < 0.01, r = 0.971). In the frequency ranges of 0.5-1.2 THz and 1.6-1.9 THz, the absorption coefficients of the highly differentiated group were higher than those of the moderately differentiated group. In the frequency range of 1.2-1.6 THz, the results were reversed, with statistically significant differences (P < 0.05). In the frequency range of 0.5-1.9 THz, the highly differentiated group had a higher refractive index than the moderately differentiated group, with a statistically significant difference (P < 0.05).
CONCLUSIONS: THz-TDS can be used to determine the pathological margins of laryngeal cancer based on the absorption coefficient and refractive index, and the magnitudes of the absorption coefficient and refractive index are related to the percentage of nuclei. The degree of differentiation of laryngeal cancer tissue can be assessed by THz-TDS. The study shows that the terahertz time-domain system is promising for applications in the diagnosis of laryngeal cancer, especially for the more accurate identification of intraoperative margins.

During crystallization, conformational changes are often accompanied by the formation of interactions. Terahertz (THz) spectroscopy exhibits strong responses to the crystalline poly(lactic acid) (PLA). Therefore, we estimate the relative crystallinity and investigate the effect of conformational transition on the vibration of PLA by THz spectroscopy. By comparing with the results of X-ray diffraction (XRD) and differential scanning calorimetry (DSC), the validity of THz spectroscopy to calculate crystallinity is verified. Furthermore, the peak intensity of PLA at 2.01 THz increases with crystallinity. Combined with Fourier transform infrared spectroscopy (FTIR), the vibrational intensity of PLA at 2.01 THz is highly correlated with the contribution of gt conformation, showing a linear relationship. In addition, the vibrational peak of PLA also reflects the interchain interactions. We believe that the increase in peak intensity with increasing crystallinity originates from the effect of the dipole-dipole interactions between the carbonyl groups. Our study demonstrates the ability of THz spectroscopy to estimate the crystallinity of PLA, and the peak at 2.01 THz shows conformational and interaction sensitivities.

Understanding the solid-state transitions of active pharmaceutical ingredients (APIs) is essential for quality control since differences in their forms affect the bioavailability of APIs. Terahertz (THz) frequency-domain spectroscopy is suitable for such an application since it can sensitively probe the lattice phonon modes originating in the crystal structures. THz absorption spectra were obtained for ezetimibe (EZT) and ezetimibe monohydrate (EZT-MH), which have similar crystalline structures and belong to the same space group. The observed absorption spectrum of EZT matched well with the solid-state density functional theory (ss-DFT)-simulated spectrum for the structures at 0 K and room temperature (modeled using constrained unit cell volumes). However for EZT-MH, the ss-DFT spectrum of the room-temperature structure showed better correlation with the experimental THz spectrum than that of the simulated spectrum of the 0 K structures, suggesting that the EZT-MH crystal has greater anharmonic character. Gibbs free-energy curves were calculated, and EZT-MH was found to be more stable than pure EZT and water in a broad temperature range. The hydrate stability may be influenced by the existence of more hydrogen bonds in EZT-MH. The hydration and dehydration of EZT in a pure API tablet and formulation tablets were monitored using a THz spectrometer with a humidity-controlled sample chamber. The effect of the excipient in the formulation tablet on hydration was successfully confirmed by showing that the solid-state transition of the API with excipients is significantly slower than that without it. Under a relative humidity of 60%, hydration of EZT in a pure EZT tablet occurred in 200 min, while the hydration of EZT in a formulation tablet was 50 times slower.

The terahertz (THz) band contains a wealth of information about vibration and rotational energy levels, most of the vibration modes between amino acid molecules are in the THz band, so it reflects many unique absorption characteristics in the THz band. The use of terahertz time-domain spectroscopy can not only effectively identify different kinds of amino acids but also distinguish various isomers of the same amino acid due to the varied vibration modes. The absorption spectra of four stereoisomers of threonine were investigated by terahertz time-domain spectroscopy (THz-TDS) and Fourier transform infrared spectroscopy. The results show that the isomers show similarity in the infrared band, while manifest evidently the similarity between enantiomers L-threonine and D-threonine, and between L-allo-threonine and D-allo-threonine, and the difference between diastereoisomer L-threonine/D-threonine and L-allo-threonine/D-allo-threonine in the terahertz band. In order to fully understand the origin of the terahertz absorption characteristics of isomer molecules, simulation calculations were carried out in combination with density functional theory to connect the vibrational modes and molecular structures, Furthermore, the unit cell configurations of L-thr and L-allo-thr and the differences between various low-frequency vibrational modes are analyzed from the perspective of hydrogen bond configuration. By further extracting terahertz optical parameters such as refractive index and imaginary part of the dielectric constant of threonine isomers, the results show that the refractive index spectrum and dielectric loss spectrum can clearly show the response characteristics of the orientation polarization of dipole inside threonine isomers in terahertz band.