Caffeine and Benzoic Acid CocrystalThe Challenge:

Cocrystals are of increasing interest due to the potential abilities to improve the physicochemical properties of the parent compounds, in particular solubility, stability and bioavailability. Synthesis via solid-based techniques (e.g. grinding) can offer enhanced selectivity as compared with that of solution-based methods. Rapid and reliable identification and monitoring of cocrystals during the development, manufacturing, and quality assurance process is critical in pharmaceutical research, PAT, and quality control.

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 both cocrystals and 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

Caffeine and Benzoic Acid Cocrystals

THz-Raman Spectra of cocrystals and mixtures of caffeine and Benzoic acid. Data courtesy Dr. Tatsuo Koide, National Institute of Health Sciences, Division of Drugs, Tokyo, Japan

Ondax THz-Raman®systems extend the range of traditional Raman spectroscopy to the terahertz/low frequency regime, where differentiation of the inter- and intra-molecular structures of cocrystals can be clearly seen. THz-Raman spectra can also be used to differentiate polymorphs, raw materials, synthetic pathways, and contaminants, useful for process monitoring, counterfeit detection and surety testing. Anti-Stokes signals add to Raman intensity and improve SNR. Ondax THz-Raman® systems provide fast, unambiguous differentiation of cocrystals and polymorphs, while preserving the complete Raman “fingerprint region” for chemical identification.


  • Simultaneous chemical AND structural analysis
  • Fast identification of cocrystals AND polymorphs , including hydrates, isomers, and conformers
  • Useful for formulation development and process monitoring
  • Non-destructive and requires no sample preparation
  • Compatible with existing Raman spectrometers
  • Simple, compact, cost-effective
  • Available in benchtop or microscope configurations at 532, 633, 785, 830 and 976nm
Caffeine Cocrystals

Caffeine Cocrystals

THz-Raman spectra of caffeine and 2-benzoic acid, showing the shift in spectra when cocrystals are formed


Carbamazepine (CBZ)

Low Frequency Raman Spectrum of Carbamazepine

Low Frequency Raman Spectrum of Carbamazepine.The strong, distinctive peaks in the low-frequency/THz-Raman region (green background) are typically higher than the traditional fingerprint range, adding signal, improving sensitivity and reliability. Peak symmetry about the excitation line also enables auto-calibration and enhanced system and data reliability.

HMTD Low Frequency THz-Raman Spectra

THz-Raman CBZ


Low frequency/THz-Raman Spectra of CBZ

Low Frequency/THz-Raman spectra of CBZ Polymorphs Forms 2 and 3, plus Hydrate


Common APIs

Low frequency THz-Raman spectra of common APIs

Complete Raman spectra of common APIs. Note stronger intensity in THz-Raman region