Overcoming optical focus issues in handheld Raman systems for analysis of pharmaceutical drug formulations

Importance of the Topic

Raman spectroscopy has emerged as a powerful tool for rapid, non-destructive analysis of pharmaceutical formulations. Handheld instruments extend this capability to field and quality control applications. However, conventional Raman sampling relies on tightly focused laser spots that may miss critical sample components and generate localized heating. The Orbital Raster Scan (ORS) approach addresses these limitations by scanning the laser over a larger area while maintaining high spectral resolution. This improvement enables consistent identification and quantification of active pharmaceutical ingredients (APIs) in complex drug formulations.

Study Objectives and Overview

This study evaluates the ORS sampling technique implemented in the Metrohm Mira M-1 handheld Raman system. The primary goals are to assess how ORS enhances spectral reproducibility, matching accuracy to library spectra, and quantitative analysis of APIs in effervescent cold medicine tablets. Comparative experiments with ORS off and on demonstrate the performance improvements in both qualitative identification and quantitative partial least squares regression models.

Methodology and Instrumentation

The experiments involved measuring effervescent cold medicine tablets containing aspirin, chlorpheniramine maleate, and phenylephrine bitartrate. Fifteen random sampling points were acquired both with static focus (ORS off) and spatially averaged ORS on, using a 1 s integration time and 75 mW laser power. Data processing included three-dimensional spectral plots for visual reproducibility assessment and partial least squares (PLS) regression for quantification of aspirin concentrations across known formulations (0 mg, 325 mg, and 500 mg).

Instrumentation Used

• Metrohm Mira M-1 handheld Raman spectrometer
• Orbital Raster Scan (ORS) sampling module
• Laser excitation: 785 nm, 75 mW
• Acquisition software: Grams AI for spectral processing and PLS regression

Key Results and Discussion

The ORS approach dramatically improved spectral consistency across random sample locations. With ORS off, peak intensities varied significantly between measurements, whereas ORS on produced tightly clustered spectra over a 3 mm scanning diameter. Quantitative PLS cross-validation for aspirin concentration yielded an R^2 of 0.9263 without ORS and an ideal R^2 of 1.0 with ORS enabled. Additionally, matching spectra to a reference library achieved Hit Quality Index (HQI) scores of approximately 0.99 with ORS, compared to 0.94–0.98 without ORS. These enhancements translate into a 95 % reduction in analysis time, requiring a single ORS scan versus fifteen static measurements.

Benefits and Practical Applications

• Enhanced reproducibility and sensitivity for heterogeneous and dark samples
• Rapid identification and quantification of APIs in pharmaceutical tablets
• Reduced risk of sample damage from localized heating
• Significant time savings through spatial averaging with a single scan

Future Trends and Applications

The integration of ORS in portable Raman devices paves the way for more robust field-deployable analytical platforms. Future developments may include automated multivariate analysis workflows, expanded libraries for complex formulations, and real-time quality control in manufacturing lines. Combining ORS with advanced chemometric techniques such as principal component analysis (PCA) could further streamline compliance with regulatory standards in pharmaceutical QA/QC.

Conclusion

The Orbital Raster Scan method in the Metrohm Mira M-1 handheld Raman system effectively overcomes optical focus limitations, delivering high-resolution, reproducible spectra over larger sample areas. This technology enhances both qualitative matching and quantitative analysis of pharmaceutical formulations, offering reliable results with significant time and cost efficiencies.