Low Frequency Raman Spectroscopy

Significance of the topic

Low-frequency Raman spectroscopy extends the spectral window down to 65 cm–1, enabling direct observation of lattice and intermolecular vibrations that lie below the conventional fingerprint region. Insights from this region are essential for detailed characterization of proteins, polymorphic forms of pharmaceuticals, phase transitions and advanced materials, improving quality control and formulation in research and industry.

Objectives and Study Overview

This study demonstrates the capabilities of the i-Raman Plus 785 nm spectrometer coupled with a BAC 102 E-grade probe to record Raman spectra from 65 cm–1 to 3200 cm–1. Key goals include:

• Accessing low-frequency modes of biomolecules and crystals
• Detecting polymorphs and pseudo-polymorphs in pharmaceutical compounds
• Monitoring real-time phase changes during thermal treatment

Methodology and Instrumentation

The experimental setup consisted of the following:

• i-Raman Plus portable Raman spectrometer with CleanLaze® 785 nm laser (linewidth <0.2 nm, up to 300 mW)
• TE-cooled back-thinned CCD detector for enhanced sensitivity
• BAC 102 series E-grade probe offering spectral coverage from 65 cm–1 to 3200 cm–1 at 4.5 cm–1 resolution

Spectra were acquired at room temperature with integration times ranging from 100 ms to 10 s and constant laser power (300 mW). Samples included L-asparagine, α-D-glucose and its monohydrate, and elemental sulfur subjected to controlled heating.

Main Results and Discussion

Access to the low-frequency region revealed distinctive features not present in the standard fingerprint window:

• For L-asparagine, three dominant Raman bands appeared below 200 cm–1, corresponding to lattice vibrations and collective modes.
• Comparison of α-D-glucose and its monohydrate showed clear shifts and intensity changes in the 65–200 cm–1 range, enabling differentiation of pseudo-polymorphs based on hydrogen-bonded lattice effects.
• During sulfur melting, a sharp peak at 83.6 cm–1 in solid α-sulfur broadened and shifted as it converted to the λ-liquid form, while the fingerprint region remained unchanged, proving the method’s sensitivity to phase transitions.

Benefits and Practical Applications

The ability to probe low-frequency vibrations offers several practical advantages:

• Enhanced polymorph detection supports pharmaceutical QA/QC and ensures correct API form.
• Real-time monitoring of phase changes aids process control in material synthesis and formulation.
• Structural analysis of proteins, semiconductors, carbon nanotubes, solar cells, minerals and pigments benefits from comprehensive vibrational data.

Future Trends and Applications

Continued development in low-frequency Raman spectroscopy is expected to drive innovations in:

• In-situ monitoring of crystallization and polymorphic transitions in manufacturing lines.
• High-throughput screening of biomolecular assemblies and supramolecular complexes.
• Non-destructive evaluation of electronic and photonic materials under operational conditions.
• Integration with automated sampling and AI-driven spectral analysis for rapid decision making.

Conclusion

The combination of the i-Raman Plus 785 nm spectrometer and BAC 102 E-grade probe provides a cost-effective, portable solution for capturing Raman signals down to 65 cm–1. This approach unlocks new opportunities in pharmaceutical polymorph analysis, phase change detection and broad materials characterization, meeting the needs of research, quality control and industrial applications.

References

1. A.M.R. Teixeira, P.T.C. Freire, A.J.D. Moreno, J.M. Sasaki, A.P. Ayala, J. Mendes Filho, F.E.A. Melo, High-pressure Raman study of L-Alanine Crystal, Solid State Communications, 2000, 116(7), 405-409.
2. P.J. Larkin et al., Polymorph Characterization of Active Pharmaceutical Ingredients Using Low-Frequency Raman Spectroscopy, Applied Spectroscopy, 2014, 68(7), 758-776.
3. E. Smith, G. Dent, Modern Raman Spectroscopy – A Practical Approach, John Wiley and Sons, 2005.
4. M.J. Pelletier, Analytical Applications of Raman Spectroscopy, Blackwell Science Ltd., 1999.