Terahertz Spectroscopy-Enabled Smart Monitoring of Drug Salt Synthesis: A Case Study on 8-Hydroquinolinium Salicylate
- 1Guizhou Institute of Metrology , , ,
- 2Guizhou Normal University , , ,
Abstract
While salt formation is a proven strategy to overcome poor aqueous solubility and facilitate the development of active pharmaceutical ingredients, real-time monitoring of this process still lacks molecular-resolution process analytical technology (PAT). Using 8-hydroxyquinolinium salicylate as a model system, this study integrates cryogenic terahertz spectroscopy, Born–Oppenheimer molecular dynamics (BOMD), and interpretable deep learning to develop a terahertz time-domain spectroscopy (THz-TDS) workflow for stage-resolved monitoring of pharmaceutical salt formation. THz measurements (80 ∼300 K) revealed the anharmonic character of the lattice vibrations, whose dominant features were reproduced and assigned by BOMD simulations. Umbrella sampling indicated a nearly barrierless proton-transfer process (ΔG‡ = 1.7 kcal/mol) with picosecond-scale shuttling dynamics. Statistical analysis of ten kinetic models confirms first-order conversion (AIC = −151.2; n = 0.99 ± 0.02) and yielded an Arrhenius activation energy of 45.2 ± 2.3 kJ/mol for predictive process optimization. Dissolution data (n = 3; mean ± SD) showed a statistically significant 2.0–2.6-fold enhancement across pH 1.2, 6.8, and 7.4, as assessed by Welch’s t test and two-way ANOVA with Tukey’s HSD test (p < 0.001). The interpretable CNN achieved 98.2% hold-out test accuracy and used SHAP to link decisions to chemical fingerprint bands. Overfitting was evaluated through spectral dimensionality reduction, dropout, a stratified training/test split, 5-fold cross-validation, leave-one-batch-out cross-validation, and external batches under shifted thermal conditions, with accuracy retained at ≥ 92.7%. These results support a proof-of-concept, interpretable THz-TDS PAT workflow with molecular-level resolution.
Related
- Carrier Dynamics in Low-Dimensional and Wide-Bandgap Materials Probed by Terahertz Magneto-Optical Spectroscopy
- Risk-Priced Radio Resources for In-Line Spectroscopy and Reaction Monitoring in Chemical Plants
- Methane monitoring in faecal headspace gas using mid-IR laser spectroscopy with a hollow waveguide gas cell
- A C2-Symmetric Biphenyl-Bridged Bis-Aurone: Synthesis, Z/E Photoisomerization, and Conformational Insights from NMR Spectroscopy and DFT Analysis
- Synthesis and optical spectroscopy of oxychloride lead tellurite glasses doped with Tm3+, Er3+ and Ho3+ ions
BibTeX
@article{song2026terahertz,
title = {{Terahertz Spectroscopy-Enabled Smart Monitoring of Drug Salt Synthesis: A Case Study on 8-Hydroquinolinium Salicylate}},
author = {Maojiang Song and Fei Yang and Ying Lu and Shijun Min and Caixia Su},
journal = {ACS Omega},
year = {2026},
month = oct,
doi = {10.1021/acsomega.6c08659},
url = {https://pubs.acs.org/acsodf/article/doi/10.1021/acsomega.6c08659/5454799/Terahertz-Spectroscopy-Enabled-Smart-Monitoring-of},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Terahertz Spectroscopy-Enabled Smart Monitoring of Drug Salt Synthesis: A Case Study on 8-Hydroquinolinium Salicylate
AU - Maojiang Song
AU - Fei Yang
AU - Ying Lu
AU - Shijun Min
AU - Caixia Su
PY - 2026
DA - 2026/10/20
JO - ACS Omega
DO - 10.1021/acsomega.6c08659
UR - https://pubs.acs.org/acsodf/article/doi/10.1021/acsomega.6c08659/5454799/Terahertz-Spectroscopy-Enabled-Smart-Monitoring-of
AB - While salt formation is a proven strategy to overcome poor aqueous solubility and facilitate the development of active pharmaceutical ingredients, real-time monitoring of this process still lacks molecular-resolution process analytical technology (PAT). Using 8-hydroxyquinolinium salicylate as a model system, this study integrates cryogenic terahertz spectroscopy, Born–Oppenheimer molecular dynamics (BOMD), and interpretable deep learning to develop a terahertz time-domain spectroscopy (THz-TDS) workflow for stage-resolved monitoring of pharmaceutical salt formation. THz measurements (80 ∼300 K) revealed the anharmonic character of the lattice vibrations, whose dominant features were reproduced and assigned by BOMD simulations. Umbrella sampling indicated a nearly barrierless proton-transfer process (ΔG‡ = 1.7 kcal/mol) with picosecond-scale shuttling dynamics. Statistical analysis of ten kinetic models confirms first-order conversion (AIC = −151.2; n = 0.99 ± 0.02) and yielded an Arrhenius activation energy of 45.2 ± 2.3 kJ/mol for predictive process optimization. Dissolution data (n = 3; mean ± SD) showed a statistically significant 2.0–2.6-fold enhancement across pH 1.2, 6.8, and 7.4, as assessed by Welch’s t test and two-way ANOVA with Tukey’s HSD test (p < 0.001). The interpretable CNN achieved 98.2% hold-out test accuracy and used SHAP to link decisions to chemical fingerprint bands. Overfitting was evaluated through spectral dimensionality reduction, dropout, a stratified training/test split, 5-fold cross-validation, leave-one-batch-out cross-validation, and external batches under shifted thermal conditions, with accuracy retained at ≥ 92.7%. These results support a proof-of-concept, interpretable THz-TDS PAT workflow with molecular-level resolution.
SN - 2470-1343
ER -