Using THz-Raman Systems for Quick and Accurate Identification of Polymorphs in Pharmaceuticals

Due to the different forms or molecular structures of a compound that influence the stability, efficacy or bio-availability of the drug, polymorphism is observed in most active pharmaceutical ingredients (APIs). These structural changes can take place during formulation, packaging, storage, and handling.

Pharmaceutical manufacturers need to identify polymorphs reliably and rapidly during all stages of production, from development to manufacturing and quality control. In this article, the advantages of THz-Raman® systems over conventional methods to identify polymorphs in pharmaceuticals are discussed.

Rapid and reliable identification of polymorphs is critical in pharmaceutical manufacturing

Rapid and reliable identification of polymorphs is critical in pharmaceutical manufacturing

Existing Techniques

The structural shifts of a compound can be determined in several ways, including X-ray diffraction (XRD), Terahertz (THz) spectroscopy, and Raman spectroscopy. Raman spectroscopy is used to monitor small band shifts in the “fingerprint” region (200 - 1800 cm-1), but this reveal subtle shifts in functional groups, and are generally hard to detect during phase or polymorphic changes.

XRD techniques can produce conclusive and quantitative analysis, but they require costly equipment and destructive off-line testing to accomplish this. THz spectroscopy can easily differentiate structural shifts, but it has a limited spectroscopic range, is moisture-sensitive, costly, and requires special sample preparation.

Coherent Systems

With Coherent THz-Raman® systems, the range of traditional Raman spectroscopy can be extended to the terahertz/low frequency regime, where inter- and intra-molecular structures can be clearly differentiated, as shown in Figure 1.

THz-Raman spectra are capable of differentiating synthetic pathways, raw materials, and contaminants. It can also be used for surety testing and counterfeit detection. Anti-Stokes signals also improve SNR, and add to Raman intensity.

Coherent THz-Raman® systems offer quick, unambiguous differentiation of polymorphs, and preserve the complete Raman “fingerprint region” for chemical identification.

THz-Raman spectra for polymorphs of various APIs showing clear differentiable peaks.

Figure 1. THz-Raman spectra for polymorphs of various APIs showing clear differentiable peaks.

Key Features

The following are the key features and advantages of Coherent systems:

  • Simultaneous chemical and structural analysis
  • Helpful for counterfeit detection or surety testing
  • Fast, reliable polymorph identification, including conformers, isomers, hydrates, and co-crystals
  • Compatible with traditional Raman spectrometers
  • Available in benchtop or microscope configurations at 532, 633, 785, and 830 nm
  • Non-destructive, and no sample preparation required
  • Simple, compact, and cost-effective

Single System Handles THz-Raman and Fingerprint Region Measurements

Due to environmental conditions and formulation/processing methods, many compounds go through structural changes. Figure 2 shows the spectra that displays two polymorphs of carbamazepine (Form 2 and Form 3).

Compared to the conventional fingerprint region (gold background), the THz-Raman range (green background) show distinct differentiating signals, improving the ease and reliability of polymorph identification.

Two polymorphs of carbamazepine (Form 2 and Form 3)

Figure 2. Two polymorphs of carbamazepine (Form 2 and Form 3)

The patented THz-Raman® Spectroscopy Systems from Coherent​ extend the range of conventional Raman spectroscopy into the THz/low frequency regime. The systems explore the same range of energy transitions as THz spectroscopy, without limiting the ability to measure the fingerprint region. This enables simultaneous analysis of chemical composition and molecular structure for advanced materials characterization.

All of the THz-Raman® systems are compact, robust, plug-and-play platforms. These easy-to-use systems offer throughput and speed at an affordable price. THz-Raman® solutions can be used for any application, due to their broad range of sample interfaces, wide selection of excitation wavelengths from 488 to 1064 nm, and optional polarization control.

THz-Raman® systems showing benchtop, probe and microscope configurations.

Figure 3. THz-Raman® systems showing benchtop, probe and microscope configurations.

This information has been sourced, reviewed and adapted from materials provided by Coherent

For more information on this source, please visit Coherent

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