Crystallization and Reaction MonitoringThe Challenge:

Measurement and control of reactions, crystallization rates and/or amorphous states is increasingly important across the chemical, pharmaceutical and electronics industries. Clear, unambiguous determination of material structure (such as polymorphs), crystallinity, and phase is essential to chemical process development, formulation and material system characterization. Most measurement modalities require special sample preparation for offline, destructive analysis and can’t provide real-time feedback.

Traditional Solutions:

Observing structural shifts of a compound can be accomplished several ways. Raman spectroscopy is used to observe small band shifts in the “fingerprint” region (200-1800 cm-1), however these reflect subtle shifts in functional groups and are difficult to detect for some polymorphs. X-ray diffraction (XRD) techniques yield extremely quantitative and conclusive analysis, but require expensive equipment and destructive off-line testing. Terahertz (THz) spectroscopy can easily differentiate structural shifts, as these signals correspond to large scale motions in the molecular and inter-molecular structure, however THz spectroscopy has limited spectroscopic range, is expensive, and can require special sample preparation.

The Ondax Solution: One Sample, One System, One Answer

Theophylline transformation low frequency waterfall spectra

Low frequency spectra can be used to monitor transformation of polymorphs. The waterfall plot at left 1 shows anhydrous theophylline before and after its transformation into a monohydrate slurry, over a period of approximately 100 seconds.

Ondax THz-Raman® systems extend the range of traditional Raman spectroscopy to the terahertz/low frequency regime, where differentiation of inter- and intra-molecular structures can be clearly seen. THz-Raman spectra can also be used to differentiate polymorphs, co-crystals, contaminants, synthetic pathways, crystal defects and as a real-time monitor of molecular structure. Anti-Stokes signals also add to Raman intensity and improve SNR. Ondax THz-Raman® systems provide fast, unambiguous real-time measurement of crystallization and phase characteristics, while preserving the complete Raman “fingerprint region” for chemical identification.


  • Fast, real-time monitoring of material structure and phase changes
  • In-situ, non-destructive and requires no sample preparation
  • Quantitative measurement of amorphous/crystalline mixtures
  • Simultaneous chemical AND structural analysis
  • Compatible with existing Raman spectrometers
  • Simple, compact, cost-effective
  • Available in probe, benchtop or microscope configurations at 532, 633, 785, 850, 976 and 1064nm
Transformation of Theophylline

Theophylline Low Frequency Raman Spectra

Spectra collected at the start and finish of the transformation of Theophylline from anhydrate to monohydrate form. (T=2s red and T=200s blue) show the disappearance of peaks at 20, 35 and 85 cm-1 in the anhydrate spectrum and the appearance of a new peak at 96 cm-1 in the spectrum of the monohydrate.

HMTD Low Frequency THz-Raman Spectra

Transformation Profile

Transformation Profile of Theophylline

The transformation time profile of anhydrate (Form II) to monohydrate (Form M) of Theophylline in a slurry, which shows the disappearance of Form II (green) and the appearance of Form M (blue). The disappearance of peaks at 20, 35 and 85 cm-1 in the anhydrate spectrum and the appearance of a new peak at 96 cm-1 in the spectrum of the monohydrate were used to monitor the transformation.


Phase Changes of Sulfur


Sulfur with callouts

Phase changes in sulfur are shown. The crystalline phase exhibits sharp peaks, indicating a high degree of order in the structure, whereas the the amorphous and liquid phases become increasingly disordered, leading to a broadening and ultimate disappearance of the distinctive peaks.