Quantification of Tablets Containing Multiple APIs Using Transmission Raman Spectroscopy

Significance of the Topic

Transmission Raman Spectroscopy (TRS) offers a rapid, nondestructive approach to quantify multiple active pharmaceutical ingredients (APIs) and excipients in solid dosage forms. By replacing traditional chromatographic techniques, TRS can streamline quality control workflows for content uniformity, assay, and product identity, reducing analysis time and resource use.

Objectives and Study Overview

This study demonstrates the quantification of five components—three APIs (phenylephrine, caffeine, paracetamol) and two excipients (magnesium stearate, Tablettose)—in a cold-and-flu tablet formulation. The goal was to build and validate predictive models that accurately determine constituent concentrations in intact tablets within seconds.

Instrumentation

A TRS100 transmission Raman spectrometer (Agilent Technologies) equipped with an 830 nm laser operating at 1.0 W was used. Samples were automatically scanned in trays, with each tablet measured for nine seconds to capture transmission Raman spectra.

Methodology

Calibration involved an orthogonal five-level design comprising 20 powdered tablet mixtures with known concentrations. Five independent validation samples with varied constituent levels were prepared similarly. Spectral preprocessing (baseline correction and normalization) highlighted spectral variations due to each component. Partial least squares (PLS) regression models were built for each constituent and evaluated via cross-validation and external validation metrics.

Results and Discussion

All five PLS models demonstrated robust predictive performance. Key findings include:

• APIs exhibited strong correlations (R² between 0.929 and 0.985) and low prediction errors (RMSEP ≤ 0.537 % w/w).
• Phenylephrine (1 % w/w) yielded acceptable accuracy despite low concentration and spectral overlap from the dominant paracetamol signal.
• Magnesium stearate showed the weakest model performance due to low Raman scattering efficiency and minimal concentration.

Validation of independent samples confirmed accurate predictions across constituents, with higher precision for stronger Raman scatterers.

Benefits and Practical Applications

Compared to HPLC and GC methods, TRS reduces batch analysis from days to under five minutes for ten tablets, eliminates chemical preparation and consumables, and requires minimal operator expertise. Simultaneous quantification of excipients enhances process monitoring, enabling detection of formulation deviations that could affect critical quality attributes such as dissolution.

Future Trends and Opportunities

Advancements may include:

• Extension to diverse dosage forms (capsules, multilayer tablets).
• Integration into continuous manufacturing and real-time release testing (RTRT).
• Application of advanced chemometric and machine learning techniques to improve model robustness and reduce calibration set size.
• Regulatory acceptance for broader PAT (Process Analytical Technology) implementations.

Conclusion

This work confirms that TRS is a powerful, efficient tool for simultaneous quantification of multiple APIs and excipients in intact tablets. It offers significant time savings, reduced resource consumption, and expanded analytical insight for pharmaceutical quality control.

Reference

1. Griffen J.; Owen A.; Matousek P. Comprehensive quantification of tablets with multiple active pharmaceutical ingredients using transmission Raman spectroscopy – A proof of concept study. Journal of Pharmaceutical and Biomedical Analysis 2015, 115, 227–282.