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.


图 1:显示不同光谱技术对应的电磁波谱。 拉曼光谱通常在可见光 (532 nm) 或近红外光 (785 nm) 中使用,而红外吸收光谱用于 5 μm 至 50 μm 的范围,太赫兹光谱用于 50 μm 至 2 mm 的范围。

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.


图 2:α 型硫和 β 型硫的拉曼光谱,显示了 0 至 200 cm-1 范围的分子间振动模式 (A) 和 200 cm-1 至 500 cm-1 范围的分子内振动模式 (B)。

硫具有 30 多种同素异构体,在生命科学和工业应用的化学过程中,发挥重要作用而得到广泛研究 [15]。 同素异形体 α 型硫具有 24 种不同的分子间振动模式,在 30 cm-1 至 100 cm-1 范围的光谱区域,使用拉曼光谱可有效检测其中的许多振动模式 [16]。 在 2013 年 SPIE 防御、安全和传感会议上提出的一篇论文中,Heyler 等人演示了如何使用太赫兹拉曼光谱检测此类振动模式 [3]。 他们还证明,当将 α 型硫样品加热至 95.6°C 以上时,该样品的形态变为同素异形体 β 型硫,随后该样品在 115.2°C 时液化。 使用该光谱可轻松检测到从 α 型形态(斜方晶形)至低序β 型形态(单斜晶形)的转变,无序度的增加导致在拉曼光谱中 100 cm-1 以下的区域变得“模糊不清”[图 2],拉曼光谱渐渐出现玻色子峰结构。 当熔化并形成 y 形态(液体)后,太赫兹拉曼域中的谱峰完全融合在一起,仅显示普通液体特有的纯玻色子带 [17]。 相比之下,形态变化并未对化学指纹区域的谱峰产生显著影响,这一点在比较 100 cm-1 以上光谱的峰位置时可以看出。 Coherent TR-MICRO 太赫兹拉曼光谱模块与正置式显微镜和光纤耦合仪搭配。图 2 显示了该系统探测到的所有光谱。 装置示意图如图 3 所示。


图 3:实验装置(用于收集 α 型硫和 β 型硫的太赫兹拉曼光谱)示意图。

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. 


图 4:Coherent TR-BENCH 台式太赫兹拉曼光谱模块。


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. 


图 5:(A) III 形态、(B) 伪多晶型二水合物形态和 (C) II 形态卡马西平的太赫兹拉曼光谱。 均在室温下测量 [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.


图 6:TR-PROBE 太赫兹拉曼探针模块,搭配Coherent的 11 英寸长不锈钢型浸入式探头。


对于不同浓度的乙醇和水溶液里的卡马西平从 III 形态向二水合物形态的转变,Inoue 等人使用该方法进行了监控 [22]。 在二水合物形态 (111 cm-1) 和 III 形态 (39 cm-1) 卡马西平的太赫兹拉曼信号非常明显,使用多元曲线解析 (MCR) 算法计算得出了图 7 所示结果。 根据该项数据,研究人员能够确定,使用 62.5% 乙醇和 37.5% 水的溶液进行反应,转换率非常高。 


图 7:乙醇和水的不同溶剂比例下,卡马西平由 III 形态转换为二水合物形态的反应动力学 [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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