Abstract
Raman spectroscopy is an established analytical method in the pharmaceutical industry. However, compact Raman devices for field deployment are still rare and the potential for further reducing the size of such instruments reaches a limit. Dual-wavelength Raman spectroscopy can be a solution to this problem and additionally provide Raman spectra with a more uniform spectral resolution across the spectral range of interest. The present article introduces spatially compressed dual-wavelength Raman spectroscopy and discusses its potential applications in pharmaceutical analysis.
Background
Over the past two decades, Raman spectroscopy has become an established analytical tool in the pharmaceutical sector. Raman techniques find applications in the lab-based analysis of pharmaceutical products, but also as a means of Process Analytical Technology (PAT).
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A key driver of Raman PAT solutions is the ongoing development of compact and robust sensors that allow inline measurements of the chemical composition with high temporal resolution and accuracy.
While laser systems with sufficient power have become very small in recent years, the potential of reducing the size of the spectrometer is limited as a certain spectral range and resolution has to be maintained.
These parameters depend on the spectrograph and the detector; in particular, on the following:
- Detector chip size
- Detector pixel size
- Spectrograph focal length
- Spectrograph slit width
- Spectrograph grating
The chip size and dispersion of the spectrograph defined by the grating and the focal length determine the spectral range that can be detected at a time. The pixel size, the grating, the focal length, and the slit width determine the resolution. For a perfectly compact device, the detector chip and the focal length must be small. To maintain sufficiently high resolution, the pixel size must be small, the focal length should be large, the slit width should be narrow, and the grating should exhibit a large number of lines per millimeter. The underlying constrained optimization problem becomes very clear. Furthermore, there are a number of limitations. The pixels cannot be smaller than a few microns and the slit width can also not be less than a few microns for physical reasons and in order to maintain sufficient signal throughput. The number of lines per mm on the grating is limited to about 5000. With a given detector and grating, the focal length of the spectrograph cannot be changed if resolution and range are to be maintained.
The common way to make a spectrograph compact is to use a special Czerny-Turner arrangement, as illustrated in Figure 1. The collimated and non-collimated light paths are crossing each other multiple times in order to make best use of the space. Similar arrangements can be found in virtually any miniature spectrometer. A further reduction in size will typically mean compromising either the spectral resolution or the spectral range.
Method
The recently proposed spatially compressed dual-wavelength Raman spectroscopy offers an opportunity to make the spectrometer more compact owing to the reduced spectral range that needs to be detected.1 In this concept, a spectrometer with a limited detection range of about 2000 cm-1 is sufficient to record the full Raman spectrum from 0 to 4000 cm-1. A custom designed two-wavelength laser used as the excitation source facilitates this. The main feature is that the two laser lines are separated by ~2000 cm-1. The spectrometer has a fixed detection range in terms of a wavelength range. This range has to be chosen such that it corresponds to different sections of the Raman spectrum depending on the excitation wavelength. This is illustrated in Figure 2 taking the wavelength combination of 680 and 785 nm as an example. It can be seen that the detection range 785-934 nm corresponds to the wavenumber or Raman shift range 0-2000 cm-1 when the sample is irradiated with 785 nm and to the range 2000-4000 cm-1 for the 680 nm laser wavelength. Therefore, recording two Raman spectra consecutively with the diff erent laser wavelengths and concatenating them yields the full Raman spectrum.
Advantages and Disadvantages
This approach has a number of advantages and disadvantages. As aforementioned, a great benefit is the spatial compression of the spectrometer, which can lead to the design of more compact instruments. This compression is at the expense of the requirement of a more sophisticated light source, i.e. the dual wavelength laser.
Another disadvantage is that the two parts of the spectrum must be acquired consecutively. This means a limitation of the method’s capabilities for its use as a means of inline process analytical technology due to the reduced temporal resolution. If the process is happening on a fast timescale, the two spectral fragments may correspond to different samples.
A benefit, on the other hand, is the homogenization of the spectral resolution across the spectrum. The resolution of a spectrometer is basically fixed in terms of wavelength, e.g. ~0.2 nm. However, the resulting wavenumber resolution, which is important for the Raman spectrum, changes with wavelength: 0.2 nm at 400 nm means 12.5 cm-1 and at 800 nm it corresponds to 3.1 cm-1. In other words, when a large wavelength range is recorded the spectral resolution varies significantly across the spectrum. This effect is reduced in dual-wavelength Raman spectroscopy as the wavelength range is compressed. Consequently, the resulting concatenated spectrum exhibits a more homogeneous resolution.
Another feature of the method is that the high-wavenumber end of the Raman spectrum is moved toward the visible spectral range, where silicon-based detectors exhibit superior quantum efficiency. Therefore, a better signal-to-noise ratio can be obtained in a shorter period of time.
Example Application
As an example, the dual wavelength Raman spectrum of a single malt Scotch Whisky (Ardbeg, 10yo) sample has been recorded. For this purpose, a dual-wavelength laser was used delivering ~300 mW continuous wave radiation at 680 and 785 nm. The resulting spectra exhibit high spectral resolution and cover all relevant regions of the Raman spectrum, i.e. the fingerprint region between 200 and 1700 cm-1, and the CH/OH stretching region from 2700 to 3700 cm-1. Whisky was chosen as an example because it represents a rather complex chemical mixture, in which a multitude of minor compounds are dissolved in a binary solution of water and ethanol. This is similar to many pharmaceutical products such as cough syrup. Moreover, the Raman spectra of Whisky are well-understood,2 so it makes a good test case. The two spectral fragments recorded with the two laser lines consecutively are displayed in Figure 3. With 680 nm excitation, the characteristic CH/OH stretching region is detected exhibiting the strong CH signatures of ethanol and the rather weak and broad OH band. When the sample is irradiated with 785 nm radiation, the fingerprint region of the spectrum can be recorded in the same wavelength range.
In conclusion, this paper described spatially compressed dual-wavelength Raman spectroscopy, which is an interesting approach that may allow building highly compact instruments for PAT solutions in the pharmaceutical and chemical industries. The method is also interesting for quality control purposes, because of its homogenized spectral resolution across the Raman spectrum. A detailed discussion of the pros and cons was provided. With the first dual wavelength laser sources being commercially available, the method is becoming more and more attractive.
Acknowledgment
The author thanks Laser 2000 GmbH (Wessling, Germany) for the loan of the dual-wavelength laser source and the fiber probe, and Sabine Wagenfeld for technical assistance. Furthermore, financial support from Deutsche Forschungsgemeinschaft (DFG) through grant KI1396/4-1 is gratefully acknowledged.
References
- J.B. Cooper, S. Marshall, R. Jones, M. Abdelkader, K.L. Wise, Spatially compressed dual-wavelength excitation Raman spectrometer, Applied Optics 53 (2014) 3333-3340.
- J. Kiefer, A.L. Cromwell, Analysis of Scotch single malt whiskies using Raman spectroscopy, Analytical Methods, 9 (2017) 511-518.
Author Biography
Prof. Dr. Johannes Kiefer is Chair Professor and Head of the division Technische Thermodynamik at the University of Bremen, Germany. In addition, he is an Honorary Professor at the University of Aberdeen, Scotland, and he holds a guest professorship of the Erlangen Graduate School in Advanced Optical Technologies (SAOT) at the University Erlangen-Nuremberg, Germany. His research interests are the areas of developing and applying spectroscopic techniques for the characterization of advanced materials and processes.