Agilent Beam Enhancer Technology for High-Speed Transmission Raman Spectroscopy

Importance of the Topic

Transmission Raman spectroscopy (TRS) enables nondestructive analysis of whole tablets and capsules, critical for ensuring content uniformity, assay, and identification in pharmaceutical manufacturing. As regulatory standards tighten and production volumes rise, rapid and accurate testing methods are essential to maintain quality control and throughput.

Study Objectives and Overview

This study evaluates the implementation of Agilent Beam Enhancer Technology to accelerate TRS measurements without increasing laser power. The primary goals were to achieve over a tenfold increase in measurement speed, maintain analytical accuracy for active pharmaceutical ingredients (APIs), and demonstrate effective content uniformity assessments across diverse tablet formulations.

Methodology and Instrumentation

• Instrumentation: Agilent TRS100 Transmission Raman Spectrometer equipped with a custom beam enhancer attachment.
• Sample Composition: Tablets containing five components—three APIs (caffeine, paracetamol, phenylephrine) and two excipients (magnesium stearate, Tablettose)—with API concentrations ranging from 0.4% to 89% w/w.
• Measurements: Each tablet was scanned at durations of 10, 1, 0.1, and 0.01 seconds, both with and without the beam enhancer.
• Data Analysis: Partial Least Squares (PLS) calibration models were developed for each constituent to evaluate analytical performance, using root mean square error of cross-validation (RMSECV) and correlation coefficients (R2).

Main Results and Discussion

• Signal Enhancement: The beam enhancer delivered an average tenfold increase in Raman signal intensity and a fivefold improvement in signal-to-noise ratio across all scan times.
• Model Performance: Caffeine PLS models at 0.01 second scans yielded R2 values of 0.963 with the enhancer versus 0.697 without. RMSECV improvements were most pronounced at shorter scan times.
• Optimal Scan Times: For most constituents, 0.1 second scans with beam enhancement provided optimal RMSECV reduction, while caffeine benefited most at a 0.01 second scan.
• Application Insights: The beam enhancer preferentially amplifies Raman scattering from the tablet’s underside, offering potential advantages in coating and thin-layer analyses.

Benefits and Practical Applications of the Method

• High-Throughput Testing: Enables rapid assessment of thousands of tablets per batch, improving manufacturing throughput and statistical confidence in content uniformity.
• Nondestructive Analysis: Maintains sample integrity, supporting inline and at-line quality control without the need for sample preparation.
• Enhanced Quality Assurance: Delivers faster, more reliable quantitation of APIs, meeting stringent regulatory requirements without increasing laser exposure.

Future Trends and Potential Applications

• Inline Process Analytical Technology: Integration of beam-enhanced TRS into continuous manufacturing lines for real-time quality monitoring.
• Expanded Formulation Analysis: Application to complex dosage forms such as bilayer tablets and coated systems, leveraging depth-resolved measurements.
• Advanced Raman Enhancements: Development of new optical geometries and photonic structures to further boost signal without raising excitation power.

Conclusion

Agilent Beam Enhancer Technology significantly accelerates Transmission Raman spectroscopy for pharmaceutical solid dosage analysis, achieving rapid, nondestructive, and accurate content uniformity measurements at speeds previously unattainable. This advancement supports high-throughput quality control, regulatory compliance, and offers a platform for future inline analytical applications.

References

1. Lostritto R. Content Uniformity (CU) Testing for the 21st Century; FDA Center for Drug Evaluation and Research.
2. Matousek P. Raman Signal Enhancement in Deep Spectroscopy of Turbid Media. Applied Spectroscopy 2007;61:845.
3. Griffen JA, Owen AW, Matousek P. Development of Transmission Raman Spectroscopy towards in line, high throughput and non-destructive quantitative analysis of pharmaceutical solid oral dose. Analyst 2015;140:107–112.
4. Zhang Y, McGeorge GM. Quantitative Analysis of Pharmaceutical Bilayer Tablets Using Transmission Raman Spectroscopy. J Pharm Innov 2015;10:269–280.