Evaluating Repeatability and Sensitivity of Transmission Raman Spectroscopy

Importance of the Topic

Transmission Raman Spectroscopy (TRS) offers bulk, non-invasive analysis of solid pharmaceuticals. Its ability to probe entire tablets—including coatings and multilayer dosage forms—makes it a powerful tool for Uniformity Content Analysis (UCA) in quality control. Compared to conventional Raman and HPLC, TRS reduces sample preparation, accelerates throughput, and supports real-time manufacturing monitoring.

Objectives and Study Overview

This work assesses the repeatability and sensitivity of the Agilent TRS100 system for quantifying a 17.00% w/w active pharmaceutical ingredient (API) in tablets. By comparing TRS predictions against HPLC reference data across a ±15% calibration range, the study establishes model performance and detection limits.

Instrumentation

The Agilent TRS100 transmission Raman spectrometer features:

• 830 nm red laser with 650 mW maximum power at the sample
• Adjustable beam diameters of 2, 4, and 8 mm; a 4 mm beam with medium collection lens was used
• Detector dynamic range optimized at 40,000 counts per accumulation
• Sample tray accommodating 20 tablets per measurement sequence

Methodology

Calibration standards spanning 85–115% of the 17.00% label claim were prepared gravimetrically and quantified by HPLC. Twenty replicate tablets per concentration level were measured by TRS. Spectral preprocessing included trimming to 200–1,800 cm–1, fluorescence baseline correction via Whittaker filtering, area normalization, and mean centering. A single-latent-variable partial least squares (PLS) model was built in SOLO and validated by 10-fold Venetian-blind cross-validation.

Main Results and Discussion

Key performance metrics:

• Calibration and cross-validation R2 of 0.967 with RMSE ~1.70% (label claim) and 1.72% CV error
• Repeatability: 96.6% of TRS predictions fell within ±4% relative error versus HPLC, meeting the ±5% industry acceptance criterion
• Limits of detection (LOD) and quantitation (LOQ) estimated at 0.85% and 2.81% w/w API, respectively

Benefits and Practical Applications

The Agilent TRS100 enables rapid, nondestructive UCA without dissolution or sampling steps. Bulk analysis through coatings streamlines QC workflows, reduces solvent usage, and accelerates tablet release, aligning with green analytical practices.

Future Trends and Potential Applications

Emerging developments include:

• Robust model transfer and calibration maintenance across instruments and production lines
• Integration into process analytical technology (PAT) for real-time release testing
• Advanced chemometric algorithms for polymorph discrimination and trace-level detection
• Continuous manufacturing monitoring with feedback control loops

Conclusion

The Agilent TRS100 delivers reliable repeatability and sensitivity for direct UCA of solid-dose pharmaceuticals. Its fast, non-destructive measurements provide a viable alternative to HPLC for content uniformity assessment, supporting modern QC and PAT initiatives.

References

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