Quantification of Tablets Containing Multiple APIs Using Transmission Raman Spectroscopy

Significance of the Topic

The ability to perform rapid, nondestructive quantification of multiple active pharmaceutical ingredients and key excipients in intact tablets represents a significant advance in routine quality control. Transmission Raman Spectroscopy (TRS) streamlines content uniformity, assay, and identity testing by eliminating sample preparation and reducing analysis time and cost.

Study Objectives and Overview

This application note evaluates TRS for simultaneous measurement of five components in a common cold and flu tablet formulation. The study aims to replace time-consuming chromatographic methods by quantifying phenylephrine, caffeine, paracetamol, magnesium stearate, and tablettose in a single nine-second measurement, covering API concentrations from 1 to 85 % w/w.

Methodology

A calibration set was designed using an orthogonal five-level mixture of 20 samples, followed by five independent validation samples. Each powdered blend was compressed into tablets, then scanned in an automated Agilent TRS100 system. Two tablets per sample were measured with an 830 nm laser at 1.0 W for nine seconds. Partial least squares regression models were developed to relate spectral features to concentration.

Used Instrumentation

• Agilent TRS100 Transmission Raman Spectrometer
• 830 nm excitation laser, 1.0 W power

Key Results and Discussion

PLS models showed strong performance for APIs and caffeine, with calibration R2 values above 0.93 and low cross-validation errors. Paracetamol and caffeine models achieved R2 > 0.98. Even phenylephrine at 1 % w/w yielded acceptable accuracy (RMSEP ~0.12 % w/w). Magnesium stearate, due to its weak Raman scattering and low concentration, exhibited the poorest model performance. Validation confirmed accurate predictions across all constituents.

Benefits and Practical Applications

TRS reduced total analysis time for ten tablets from approximately two days to under five minutes without chemical reagents or extensive operator training. Simultaneous excipient quantification adds value for process monitoring and batch consistency assessment, supporting quality-by-design and PAT initiatives.

Future Trends and Opportunities

Future developments may extend TRS to more complex formulations, integrate real-time monitoring in manufacturing lines, and leverage advanced chemometric and machine-learning algorithms to handle low-scattering components. Portable TRS instruments and automated calibration maintenance could further enhance in-process and at‐line quality control.

Conclusion

Transmission Raman Spectroscopy offers a fast, nondestructive, and cost-effective alternative to chromatographic assays for quantifying multiple APIs and excipients in intact tablets. This approach supports accelerated testing, improved resource utilization, and enhanced process understanding.

Reference

1. J. Griffen, A. Owen, P. Matousek. 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.