Combined LIBS and Raman Spectroscopy: A Versatile Analytical Tool for Pharmaceutical Analysis

Monday, April 1, 2024

Abstract

The comprehensive chemical characterization of a pharmaceutical powder or liquid requires determining both the elemental and molecular composition. Unfortunately, there is no single method that can provide all the information desirable. This article highlights the recent development of an experimental approach that allows the simultaneous application of laser-induced breakdown spectroscopy (LIBS) and Raman spectroscopy and discusses its potential use for pharmaceutical analysis.

Introduction

Elemental and molecular analysis plays a critical role in ensuring the quality, safety, and efficacy of pharmaceutical products throughout their lifecycle, from development and manufacturing to regulatory approval and commercialization. Key tasks of such analysis include:

Quality control: Pharmaceutical products must meet strict quality standards to ensure safety, efficacy, and consistency. Elemental and molecular analysis helps verify the composition and purity of active pharmaceutical ingredients (APIs) and excipients, ensuring that products meet regulatory requirements and quality specifications.
Characterization of APIs: Elemental and molecular analysis provides detailed information about the chemical composition, structure, and properties of APIs. This information is essential for characterizing the identity, purity, and stability of drug substances, and facilitating the development, formulation, and manufacturing of pharmaceutical products.
Detection of impurities: Pharmaceuticals may contain impurities from various sources, such as raw materials, synthesis intermediates, or degradation products. Elemental and molecular analysis enables the identification and quantification of impurities, including elemental impurities (e.g., heavy metals) and organic impurities (e.g., related substances, degradation products), ensuring product safety and regulatory compliance.
Formulation development: Elemental and molecular analysis assists in the formulation development of pharmaceutical products, such as tablets, capsules, and injectables. By understanding the chemical composition and behavior of drug substances and excipients, formulators can optimize formulation parameters, such as drug loading, compatibility, and stability, to achieve desired product performance and characteristics.
Process monitoring and optimization: Elemental and molecular analysis is used for monitoring and optimizing manufacturing processes in the pharmaceutical industry. By analyzing raw materials, intermediates, and finished products, manufacturers can identify process deviations, troubleshoot issues, and improve process efficiency and yield.
Regulatory compliance: Regulatory agencies, such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), require comprehensive analytical data to assess the safety, efficacy, and quality of pharmaceutical products. Elemental and molecular analysis provides essential data for regulatory submissions, product registration, and compliance with Good Manufacturing Practices (GMP) and other regulatory requirements.

While there is not a single method that can achieve both molecular and elemental analysis simultaneously with high specificity and sensitivity, some analytical techniques can provide complementary information about both molecular and elemental composition. Raman spectroscopy and laser-induced breakdown spectroscopy (LIBS) seem to be a perfect match in this context.^1,2 Moreover, both methods can provide rapid measurements and do not need a specific sample preparation or treatment; hence, they are perfectly suited for process monitoring in real-time.

Combining Raman and LIBS

The basic experimental setups of LIBS and Raman look rather similar: a laser source, some lenses and optical filters, a spectrograph, and a detector. However, the requirements for generating and detecting useful signals are extremely different. In LIBS, a short, high-intensity laser pulse atomizes and ionizes a small amount of the material and creates a local plasma, the optical emission of which is then analyzed in a spectrometer. In Raman, on the other hand, long pulses with low intensity or continuous wave laser radiation is used to produce a signal via inelastic light scattering. Moreover, LIBS signals are rather strong and can be seen with the naked eye while Raman signals are inherently weak. So, combining LIBS and Raman in a way such that both signals are generated and detected more or less simultaneously is not straightforward.

Figure 1. Schematic of experimental setup for simultaneous Raman/LIBS measurements. iCCD = intensifi ed charge coupled device camera. The insets A and B illustrate the temporal shapes of the laser pulse before and after the pulse stretcher unit, respectively.

It is possible though, as demonstrated recently.³ When a pulsed laser is complemented with an optical pulse stretcher and an optical delay line it can deliver a sequence of two laser pulses: a long one with low intensity and high energy, which is perfectly suited for Raman spectroscopy, and a second, short one with high intensity for LIBS. Combining this light source with an advanced signal detection strategy allows not only generating Raman and LIBS signals within a very short time interval (on the order of 100 nanoseconds), but also acquiring them with a single spectrometer and detector. The schematic experimental setup is illustrated in Figure 1, which also gives a qualitative impression of the pulse shaping performance of the unit with the pulse stretcher and the delay line. A single Gaussian pulse goes in and two pulses suitable for generating Raman and LIBS signals come out. For a detailed account of the specifications and a discussion of the signal detection scheme, the reader is referred to the original paper,³ which is available for open access.

Raman/LIBS Analysis in the Pharmaceutical Sector

The described Raman/LIBS approach is a very promising method for comprehensive chemical analysis at different stages of the lifecycle of pharmaceutical products. As outlined above, useful applications may include quality control of products, impurity detection, and characterization of APIs. Nevertheless, these tasks do not usually require a rapid plus simultaneous elemental and molecular characterization as the sample does not change with time. The key feature of the proposed method, however, is the real-time capability. Consequently, process monitoring at different stages such as analyzing raw materials, intermediates, and finished products seems to be the most promising area.

Figure 2. Schematic stick Raman/LIBS spectrum of the API
naproxen. The Raman contributions are displayed red, while the LIBS signatures are blue.

The two signals are generated within about 100 ns, which is short enough to consider the measurement simultaneous and instantaneous. Moreover, both signals are merged into a single spectrum, which can easily be evaluated using state-of-the-art chemometric techniques. In order to give an impression of what such a combined Raman/LIBS spectrum may look like, Figure 2 shows a schematic stick spectrum of the nonsteroidal anti-inflammatory drug naproxen, which is commonly used to treat pain, inflammatory diseases such as rheumatoid arthritis, and fever. For clarity, only the main expected Raman and LIBS signals are plotted. Interestingly, there is virtually no spectral overlap between the two signal types despite the merged acquisition. This suggests that the data evaluation should be straightforward in a real-world application. Of course, a realistic situation would mean additional substances like excipients and impurities. This would certainly make the spectrum, the Raman spectrum (0-4000 cm-1) in particular, richer and more complex. Anyway, modern off-the-shelf data evaluation routines can easily handle this complexity.

Conclusion

In conclusion, combining Raman and laser-induced breakdown spectroscopy is capable of measuring the elemental and molecular composition of a sample simultaneously and within a very short time interval. Suggested measurement times shall be on the order of a few microseconds, while the signals are generated within about 100 nanoseconds. Moreover, as individual methods both Raman and LIBS have been deployed in all kinds of extreme environments (from deep sea to planet Mars), which highlights their robustness and reliability. This makes their combination a very promising tool for in situ applications such as process monitoring in the pharmaceutical and chemical sectors. The development of a turn-key Raman/LIBS instrument is the next step targeting qualitative and quantitative analysis in real-time.

This work was supported by Deutsche Forschungsgemeinschaft (DFG) through grant KI1396/3-2.

Author Details

Johannes Kiefer - Universität Bremen, Technische Thermodynamik, Badgasteiner Str. 1, 28359 Bremen, Germany

Prof. Dr. Johannes Kiefer is Chair Professor and Head of the Engineering Thermodynamics department at the University of Bremen, Germany. His research interests are the areas of developing and applying spectroscopic techniques for the characterization of advanced materials and processes.

Publication Details

This article appeared in American Pharmaceutical Review:

Vol. 27, No. 3

April 2024

Pages: 16-18

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