Low-frequency Raman spectroscopy

Importance of the Topic

The ability to probe low-frequency vibrational modes down to 65 cm⁻¹ significantly expands the analytical power of Raman spectroscopy. By capturing molecular lattice and intermolecular interactions, this spectral range supports advanced applications in protein characterization, polymorph identification, and phase transition monitoring. Such insights directly impact pharmaceutical development, materials science, and quality control processes by improving sensitivity and discrimination of structurally similar compounds.

Objectives and Study Overview

This application note demonstrates the use of a portable Raman system equipped with a low-frequency probe to:

• Characterize amino acids across the full 65–3200 cm⁻¹ range
• Differentiate pharmaceutical polymorphs and pseudo-polymorphs below 200 cm⁻¹
• Monitor solid–liquid phase transitions in real time

The work highlights how extending Raman detection into the low-frequency region augments molecular information beyond traditional fingerprint analysis.

Methodology and Instrumentation

An i-Raman Plus 785S spectrometer with patented CleanLaze® technology and a BAC102 E-grade fiber probe were used. Key parameters included:

• 785 nm laser excitation (≤0.2 nm linewidth, up to 300 mW)
• Spectral coverage from 65 to 3350 cm⁻¹ at 4.5 cm⁻¹ resolution
• TE-cooled, back-thinned CCD detector
• Integration times between 0.1 and 10 s

Data were acquired at room temperature, varying integration times to optimize signal intensity for different sample types.

Main Results and Discussion

• Amino Acid Spectra: L-asparagine exhibits three intense low-frequency bands below 200 cm⁻¹, underscoring the necessity of sub-400 cm⁻¹ data for full structural interpretation.
• Polymorph Detection: α-D-glucose and its monohydrate form display distinct low-frequency signatures, allowing clear differentiation of pseudo-polymorphs that share identical chemical compositions.
• Phase Change Monitoring: Upon heating α-sulfur past its melting point, the prominent low-frequency peak at 83.6 cm⁻¹ broadens and shifts, indicating transformation to the λ-form; fingerprint region remains largely unchanged.

These findings confirm that low-frequency Raman signals provide unique markers for solid-state structures and phase behavior not observable in conventional Raman windows.

Benefits and Practical Applications

By incorporating low-frequency detection, the described system offers:

• Enhanced specificity for protein conformational studies
• Rapid, non-destructive polymorph screening in pharmaceutical QC
• Real-time monitoring of crystallization and melting processes
• Broader applicability to semiconductor lattices, carbon nanotubes, solar cell materials, and minerals

This versatility facilitates more informed decision-making in research, production, and quality assurance.

Future Trends and Potential Applications

Advances in detector sensitivity and probe miniaturization are expected to enable even lower-frequency access and in situ analysis under extreme conditions. Emerging fields may include real-time monitoring of battery electrode phases, dynamic studies of biomolecular assemblies, and on-line process control in continuous manufacturing.

Conclusion

Extending Raman spectroscopy into the 65–200 cm⁻¹ region significantly enriches structural and phase information. The portable i-Raman Plus system combined with the E-grade probe demonstrates robust performance for amino acid analysis, polymorph discrimination, and phase transition detection. Such capabilities address critical needs across pharmaceutical development, materials science, and industrial analytics.

Reference

• Teixeira A.M.R., Freire P.T.C., Moreno A.J.D. et al. High-Pressure Raman Study of l-Alanine Crystal. Solid State Communications 2000, 116(7):405–409.
• Larkin P.J., Dabros M., Sarsfield B. et al. Polymorph Characterization of Active Pharmaceutical Ingredients (APIs) Using Low-Frequency Raman Spectroscopy. Applied Spectroscopy 2014, 68(7):758–776.
• Golichenko B.O., Naseka V.M., Strelchuk V.V. et al. Raman Study of L-Asparagine and L-Glutamine Molecules Adsorbed on Aluminum Films in a Wide Frequency Range. Semiconductors Physics, Quantum Electronics & Optoelectronics 2017, 20(3):297–304.
• Smith E., Dent G. Modern Raman Spectroscopy: A Practical Approach, 2nd ed.; John Wiley & Sons, 2019.
• Pelletier M.J. Analytical Applications of Raman Spectroscopy, 1st ed.; Blackwell Science: Oxford, 1999.