An Introduction to THz-Raman Spectroscopy


The terahertz (THz) region of the electromagnetic spectrum, from roughly 0.15 THz to 6 THz (5 cm-1 to 200 cm-1), has long been researched as a means of investigating low-energy vibrational modes of materials. This region is particularly attractive to spectroscopists studying intermolecular vibrations within crystals [1], yielding important information about the molecular orientation that governs many key properties of materials. On the most fundamental level, THz spectroscopy is an extension of far-infrared (FIR) absorption spectroscopy. In practice, it is far more challenging to implement because it is at the extreme low-end of the optical frequency domain and extreme high-end of the frequency domain for electronics. That is why this region of the spectrum is often referred to in the published literature as the “terahertz gap” [2]. Currently, commercial THz spectroscopy systems are available on the market, but most are extremely expensive and difficult to use due to the complexity of the ultrafast lasers typically required to generate THz radiation and susceptibility of samples to moisture.

Fortunately, direct absorption of terahertz radiation is not the only way to access THz-domain vibrational modes as many are also Raman active. Raman scattering results from the inelastic scattering of photons, not absorption, therefore decoupling the excitation wavelength from the vibrational modes under investigation. In traditional Raman, the spectral range of 200 cm-1 to 1800 cm-1 represents the “chemical fingerprint,” since most intramolecular vibrations occur in this frequency range. In a complementary way, the THz-Raman™ (also referred to as low-frequency Raman or LFR) region, from 5 cm-1 to 200 cm-1, provides a “structural fingerprint” that corresponds mainly to inter-molecular vibrations, or lattice/phonon modes of the material. Figure 1 shows the relative wavelength locations where THz spectroscopy (50 μm to 2 mm), IR spectroscopy (5 to 50 μm) and THz-Raman spectroscopy occur within the electromagnetic spectrum. Figure 2 correspondingly shows the relative locations of the chemical and structural fingerprints of a typical Raman spectrum.

Raman spectroscopy historically has been challenging to implement in the THz-domain because the inelastic scattering (Raman shift) is orders of magnitude weaker than the elastic scattering (Rayleigh), making it hard to adequately filter out the Rayleigh scatter. As a result, it was difficult to resolve signals with Raman shifts very close to the Rayleigh line (0 cm-1). This situation completely changed with revolutionary developments in volume holographic notch filters that have made it easy to directly measure Raman shifts as small as 5 cm-1 with just a simple monochromator featuring high optical efficiency [3]. This breakthrough has resulted in a paradigm shift for low-frequency Raman: from a relative novelty requiring complex multistage monochromators, to self-contained spectrometers that any scientist can set-up in a matter of minutes, as well as plug and play add-on modules for existing instruments. For example, these THz-Raman modules include immersion probes for reaction monitoring, microscope platforms for mapping the phase of samples, and well plate readers for high-throughput screening applications.


図1: 様々な分光技術の位置を示す電磁波スペクトル。ラマン分光は通常、可視光(532 nm)または近赤外線(785 nm)で行われ、赤外線吸収分光は5~50 μm、THz分光は50 μm~2 mmで行われます。

THz-Raman System Requirements

Every THz-Raman system has four things in common:

  1. A wavelength stabilized laser source
  2. Narrowband (< 5 cm-1) spectral clean-up filters
  3. Narrowband (< 5 cm-1) Rayleigh scatter blocking filters
  4. A spectrometer that can detect the low frequency signals

The Rayleigh filter, a +/- 5 cm1 bandwidth notch filter, should be the limiting factor to how low into the THz-domain the system can detect. However, for the Rayleigh filter to function properly, it is critical that the laser’s output spectrum be extremely stable, have a very narrow linewidth, and exhibit extremely low noise from amplified spontaneous emission (ASE) or side bands within the transmission region of the notch filters. It is also essential that the center wavelengths of both the filters and the laser remain “spectrally synchronized” to one another during operation to avoid leaking of the Rayleigh signal and saturation of the spectrometer’s detector. As an integrated manufacturer of lasers, filters and optical systems, Coherent spectrometers and modules are all designed to perfectly maintain this synchronization, ensuring robust, easy to operate performance at all times.

An additional advantage of these systems is that since Raman spectra are measured as a relative shift from the laser frequency, THz-Raman systems can use lasers at any wavelength in the visible or near infrared (NIR) to probe these low-energy vibrational modes, eliminating the need for a THz laser source. This enables a much simpler and less-costly spectral collection scheme, allowing for the use of glass optics and fibers, compact and inexpensive diode and diode-pumped solid-state (DPSS) laser sources, and silicon detectors and detector arrays. THz-Raman systems are also capable of detecting anti-Stokes Raman shifts, less than -5 cm-1, which provide additional information about the sample, including local effective temperature. Therefore THz-Raman systems can simultaneously measure both the chemical and structural fingerprints of materials with high throughput in a single measurement.

The combined benefits of THz spectral information with the ease of use of Raman spectroscopy now make it a powerful solution for applications that are interested in both the chemical and structural properties of materials. THz-Raman has been rapidly adopted by the pharmaceutical industry [4-9] and is also getting traction in polymers [10], semiconductors [11-13], and biomedical diagnostics [14].


Low-frequency Vibrational Modes

As described above, low-frequency peaks result from intermolecular vibrations such as phonon modes and lattice vibrations. In crystalline samples, the position (shift) of the peaks are specific to the composition (chemical and structural) details of the crystal. And the bandwidth and intensity of these sharp low-frequency peaks are directly related to the degree of structure (crystallinity) of the sample. In contrast, amorphous solids and liquids have a broad unresolved peak known as the boson peak. Therefore, the THz-Raman spectrum is a useful tool to quantitatively analyze sample crystallinity and to classify different allotropes and polymorphs. Although polymorphic analysis is a more popular application, it is easier to understand by examining the THz-Raman spectra of different allotropes to better illustrate the properties of low-frequency vibrational modes.


図2: α-硫黄とβ-硫黄のラマンスペクトル。200 cm-1の分子間振動モード(A)と200 cm-1〜500 cm-1の分子内振動モード(B)を示しています。

30以上の同素体を持つ硫黄は、ライフサイエンスと産業応用の両方で幅広い化学加工方法において重要であることから、広範囲にわたって研究されています[15]。同素体のα-硫黄は24種類の分子間振動を持ち、その多くが30 cm-1 - 100 cm-1領域のスペクトルでラマン活性を示すことが示されています[16]。2013年のSPIE Defense, Security, and Sensingカンファレンスで発表された論文で、Heylerらは、これらの振動モードをTHz-Ramanを使って検出する方法を示しました[3]。さらに、α-硫黄の試料を95.6℃以上に加熱すると、同素体であるβ-硫黄に形状変化し、115.2℃で液化することを明らかにしました。α型(斜方晶)から低秩序β型(単斜晶)への遷移は、乱れの増大により100 cm-1以下のラマン分光のモードが「ぼやけ」、よりボゾンピーク構造に近づいていることから容易に検出できました[図2]。融解してy型(液体)になると、THz-Raman領域の構造モードは完全に融合し、通常の液体に典型的な純粋なボソンバンドのみを示すようになります[17]。一方、化学指紋領域のモードは、100 cm-1以上のスペクトルのピーク位置を比較すると明らかなように、形状変化の影響をあまり受けていないことがわかりました。図2のスペクトルはすべて、正立顕微鏡とファイバー結合型分光器に取り付けられたCoherent TR-MICRO THz-Ramanモジュールを用いて収集されたものです。図3にセットアップの模式図を示します。


図3: α-硫黄とβ-硫黄のTHz-Ramanスペクトルを収集するために使用した実験装置の概略図。

The THz-Raman unit contains a single frequency excitation laser, precisely matched to ultra-narrow-band (volume holographic) laser line and notch filters. The notch filters are specifically designed to ensure maximum throughput of the Raman scatter while also attenuating the Rayleigh scatter with an optical density (OD) greater than 9, enabling their use with inhomogeneous samples. Finally, the remaining Raman scatter is coupled to a spectrometer through a fiber optic cable. A more detailed explanation of the optical design is available in the conference proceedings [3].


Applications in Pharmaceuticals

Polymorphism is a critical and common characteristic of active pharmaceutical ingredients (APIs). It has a direct impact on drug substance bioavailability, manufacturability, and quality/performance [18]. Since polymorphic compounds have the same base molecular composition but different bulk structural orientations, THz-Raman is far better suited than conventional infrared (IR) and Raman spectroscopies to determine the polymorphic form. For the sake of completeness, it should be noted that in some cases, polymorphic differences can lead to subtle peak shifts in the chemical fingerprint region of the Raman spectra [19,20] due to damping of intramolecular vibrations. That said, the spectral changes in the low-frequency range tend to be far more pronounced (up to 10x stronger) and more easily differentiable without the need for complex chemometric analysis. Additionally, as Larkin et al. demonstrated in a 2014 article published in Applied Spectroscopy, “Low-frequency Raman spectra of large aromatic species typical of APIs provide remarkably intense bands below 200 cm-1 with complex spectral features [9].” They went on to explain that these bands are typically an order of magnitude more intense than those of the surrounding excipients in the same frequency range, which provides the ability for THz-Raman to directly measure “crystalline structure, crystalline disorder, and amorphous states,” with enhanced sensitivity. 


図4: Coherentのベンチトップ型THz-Ramanモジュール「TR-BENCH」。


Between the study mentioned above [9] and a follow-up study published in 2015 [10], researchers at Bristol-Myers Squibb have provided a detailed analysis of the low-frequency Raman bands for polymorphs of some common APIs. In those two publications, they analyzed indomethacin, carbamazepine, caffeine, theophylline, and apixaban. Larkin et al. used a benchtop THz-Raman sampling system, similar to the TR-BENCH currently available from Coherent shown in figure 4. The TR-BENCH has the same internal optical architecture as the TR-MICRO discussed in the previous section. As an example of this research, figure 5 shows the THz-Raman spectra of three different forms of carbamazepine. 


図5: カルバマゼピンの(A)III型、(B)擬似多形二水和物型、(C)II型におけるTHz Ramanスペクトル。すべて室温で測定[8]。


In recent years, THz-Raman spectroscopy has transitioned out of research laboratories and into pharmaceutical process monitoring applications, often referred to as process analytical technology (PAT) [21-24]. In process applications, fiber-coupled THz-Raman probes enable in-line, on-line, and at-line measurement, where the analyzer can be remote from the sample and does not need the sample to be captured and brought to the analyzer. Depending on the demands, the probe tip can be designed with a short working distance for direct immersion into a reaction chamber through an access port, or with a longer working distance to collect spectra through a viewing window. Figure 6 shows an example of the TR-PROBE with an immersion probe tip attached.


図6: Coherent製11インチ長ステンレス製イマージョンチップが付属したTHz-RamanプローブモジュールTR-PROBE。


井上氏らは、この方法を用いて、エタノールと水の濃度を変えて、カルバマゼピンIII型からカルバマゼピン二水和物への転移を監視しました[22]。図7の結果は、カルバマゼピン二水和物(111 cm-1)とカルバマゼピンIII(39 cm-1)のTHz-Ramanバンドが支配的で、多次元曲線解決(MCR)アルゴリズムを用いて計算した場合のものです。このデータをもとに、エタノール62.5%と水37.5%の溶液を用いた反応が最も早く変換されることを突き止めました。 


図7: エタノールと水の溶媒比率を変化させた場合のカルバマゼピンIII型からカルバマゼピン二水和物への変換の濃度キネティクス[21]。

The Future of THz-Raman

While the pharmaceutical industry was the first to widely adopt THz-Raman, other sectors are using it to analyze crystallinity and polymorphism as well. A recent example is the use of THz-Raman to explore the relationship between mobility and strain [25], as well as charge transport and low-frequency vibrations [12] in organic semiconductors. It is also being used to analyze phonon modes in quantum dots [11], and layered semiconductor alloys [13]. Recently studies have been also published on polymer crystallization [10] and the formation of lamella during the cooling process [26], providing critical information about structural properties of products for the polymer industry. Perhaps the most exciting up and coming applications of THz-Raman are in biology and biomedical diagnostics. At the 2019 SPIE BiOS conference in San Francisco, Marble et al. presented the first talk on using THz-Raman for biological molecules [14], and a year later, THz-Raman was already being explored as a potential diagnostics tool for COVID-19 [27].



THz-Raman has repeatedly been shown to provide users with robust and simultaneous structural and chemical compositional information. There is no doubt that the applications will continue to grow and expand as THz-Raman analyzers transition out of the lab and into industrial settings. It is inevitable at this point that researchers will continue to find new uses for the highly differentiating information revealed by THz-Raman that have not yet been conceived. For additional information on THz-Raman instrumentation, applications, or capabilities, please visit www.thz-raman.com or request a consultation with an applications scientist via our website www.coherent.com



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