University of Copenhagen and Monash University Researchers Develop New Raman Technique to Analyze Packaged Drugs

In a recent study, a team of researchers from the University of Copenhagen and Monash University showed how low-frequency Raman (LFR) spectroscopy can potentially be a valuable technique in pharmaceutical analysis. This study, which was published in Measurement and led by Kārlis Bērziņš and Ben J. Boyd, demonstrates how LFR spectroscopy can be used to enhance the structural characterization of drugs through packaging materials (1).

University of Copenhagen | Image Credit: © borisb17 - stock.adobe.com

Raman spectroscopy has been used in several pharmaceutical analysis applications. In particular, it has been used in on-line process monitoring and analysis (2). Several advanced analytical techniques have been built from Raman spectroscopy, including LFR spectroscopy. LFR spectroscopy is a vibrational spectroscopic technique that allows analysts to interpret structural chemical information based on the sample’s vibrational characteristics (3). The technique has been shown in previous studies to be optimal for enantiomeric identification and crystalline phase identification (3).

In this study, the research team explored three variants of spatially offset LFR spectroscopy, comparing them with traditional mid-frequency Raman (MFR) techniques, which cover the fingerprint region (300–1800 cm⁻¹) (1). The configurations examined in this study include defocusing displacement, point-like offset, and transmission geometries.

The researchers tested LFR on different types of packaging and drug mixtures. They found that LFR consistently outperformed MFR in areas such as signal strength, measurement speed, and structural sensitivity (1). The researchers were able to switch between different spatially offset optical configurations using a modular instrument setup, which allowed them to directly compare their performance (1).

This flexibility helped the researchers conduct comprehensive testing across multiple practical conditions. Notably, the defocusing and point-like offset configurations emerged as the most viable options for analyzing bottle-sized pharmaceutical containers (1). Transmission mode was limited to small transparent containers with path lengths under 1.5 cm (1).

There are several important takeaways that emerged from this study. The scattering propensity of the LFR domain was excellent, the researchers wrote. This allowed for the resolution of detailed drug features through both plastic and dark glass packaging, which are materials that often obscure or distort signals in MFR-based Raman methods (1). The result was that the signal clarity of LFR was improved. In turn, the improved signal clarity reduced the time needed for accurate measurements (1).

In many scenarios, LFR spectroscopy delivered stronger and more detailed spectral data in a fraction of the time required by MFR methods (1). This has major implications for pharmaceutical quality control, where time and accuracy are critical.

Another aspect to this study worth mentioning is the ability of LFR to conduct semi-quantitative analysis of drug mixtures. The researchers demonstrated that LFR can distinguish between anhydrous and hydrated forms of caffeine, which are differences that were indistinguishable using conventional fingerprint Raman techniques (1).

Moreover, the LFR configurations enabled real-time observation of dynamic structural changes within packaged pharmaceuticals. This included the monitoring of temperature-induced transformations. By reducing measurement times and increasing the ability to detect subtle structural changes, spatially offset low-frequency Raman spectroscopy (SOLFRS) can potentially be used to enhance quality assurance protocols in pharmaceutical manufacturing (1). The rapid, non-destructive nature of SOLFRS also makes it suitable for deployment in continuous production lines.

As the pharmaceutical industry continues to seek faster, safer, and more reliable analytical tools, this approach to Raman spectroscopy marks a promising advancement. The authors envision the development of hand-held, LFR-enabled devices tailored for field use, potentially transforming how medicines are verified and monitored across the global supply chain (1).

References

1. Bērziņš, K.; Krog, L. S.; Boyd, B. J. Non-invasive Structural Analysis of Packaged Pharmaceuticals Using Different Variants of Spatially Offset Low-frequency Raman Spectroscopy. Measurement 2025, 252, 117360. DOI: 10.1016/j.measurement.2025.117360
2. Vankeirsbilck, T.; Vercauteren, A.; Baeyens, W.; et al. Applications of Raman Spectroscopy in Pharmaceutical Analysis. TrAC Trends Anal. Chem. 2002, 21 (12), 869–877. DOI: 10.1016/S0165-9936(02)01208-6
3. Aviv, H.; Damle, V. H.; Tischler, Y. R.; et al. Low-frequency Raman Spectroscopy - A Versatile Technique for Material Characterization and Detection Overview of Raman Spectroscopy. The Israel Chem. Chem. Eng. 2023, 9, ASAP. DOI: 10.51167/ice000016