Laser-Induced Breakdown Spectroscopy of Pharmaceutical Products

Johannes Kiefer - Universität Bremen, Technische Thermodynamik - Badgasteiner Str. 1, 28359 Bremen, Germany - Email: [email protected]

Abstract

Analytical methods that can determine the quality of pharmaceutical products fast and without the need for sample preparation are highly desirable. Laser-induced breakdown spectroscopy (LIBS) is such a tool. Within fractions of a second it can provide the elemental composition, e.g. at a specific location on a tablet. Scanning the measurement position across the specimen even allows mapping virtually all chemical elements. This article provides an overview of the working principle of LIBS and features its applications to pharmaceutical products.

Introduction

Laser-induced breakdown spectroscopy (LIBS, also known as laser-induced plasma spectroscopy, LIPS) has been a well-established analytical method for many decades. Its wide use has multiple reasons including a rather simple and robust experimental setup as well as straightforward data evaluation. In a typical LIBS experiment, the pulse from a Q-switched laser is focused on the sample and in the vicinity of the focal spot, the light intensity is high enough to cause atomization and ionization of the material, which can be a gas, liquid or solid. A plasma is formed, which emits characteristic radiation that can be analyzed in a spectrometer. A great benefit of LIBS is that it requires no sample preparation or treatment. Moreover, a LIBS spectrum contains signatures from virtually all elements at the same time.

These features have made LIBS a very popular technique that has been applied to all kinds of samples (from food via gases to minerals) and it has been deployed in all kinds of environments (from deep sea to planet Mars). In this article, we focus on LIBS applications to pharmaceutical products.

LIBS in a Nutshell

Figure 1 (upper) shows a schematic lab setup in order to illustrate the experimental simplicity of LIBS. The laser pulses are focused by a lens to create a breakdown at the measurement position. The high intensity at the focal spot leads to ionization through multiphoton absorption and electron avalanche ionization. The free electrons are further excited by inverse bremsstrahlung so that the created plasma reaches a high temperature. After the laser pulse, the electrons emit a nonspecific continuum of radiation through bremsstrahlung and once they have recombined with the ions a species-specific spectral signature is observed. An example spectrum recorded in room air is displayed in Figure 1 (lower). It clearly shows the spectral signatures of the main constituents, nitrogen and oxygen, and even a small peak of hydrogen originating from the ambient moisture is visible.

For field deployment and industrial use, the experimental setup can be made very compact. It can come as a handheld instrument or a benchtop device. The benchtop devices are very useful for pharmaceuticalproducts as they can be arranged as a scanning microscope and will produce a map with chemical contrast similar to energy dispersed X-ray (EDX) mapping but without sample preparation and vacuum. 

The data analysis can be performed using univariate methods and a calibration experiment, but nowadays multivariate methods are more common. In principle, the entire chemometric toolbox with techniques ranging from principal component analysis (PCA) via regression approaches to artificial neural networks (ANN) and deep learning algorithms can be used. The selection of a proper method should consider the availability of training data, the desired information, and the quality of the spectra.

LIBS Analysis of Pharmaceutical Products

For completeness it should be noted that LIBS can also be used as a means of process analytical technology (PAT). However, in the present article we focus on applications to pharmaceutical products. There are a number of questions that can be answered by LIBS:

• Does the product contain the correct constituents? The LIBS spectrum represents a chemical (elemental) fingerprint of the sample. The detailed elemental composition can tell whether or not the desired active substances and excipients are present. Of course, many different substances contain the same chemical elements, but their relative concentrations and the resulting LIBS signature is likely unique.
• Does the product contain contaminants? Unwanted substances such as solvents or lubricants from the production process can cause harm to the consumer of a pharmaceutical product; hence, the need to be detected even at low concentration levels. LIBS is capable of detecting elements down to ppb level (depending on the element and the data acquisition).
• Is the active ingredient homogeneously distributed in a tablet? The homogeneous distribution of the active ingredients can be extremely important; for instance when tablets can be split into smaller parts in order to provide the right dosage. LIBS can map the elemental composition across the surface of a tablet and hence identify inhomogeneity of any constituent. 

Aside from the questions LIBS can answer, there are a couple of points to be considered. As said before, LIBS is typically performed using Q-switched lasers. They emit pulses with a duration of a few nanoseconds depending on the individual laser type. Usually such lasers provide repetition rates on the order of 1-50 Hz, which limits the measurement frequency. In recent years, pico- and femtosecond lasers have become increasingly popular in LIBS. They allow higher rep rates (up to MHz), but the experiment becomes more complicated due to the conditions required for stable laser operation.

Despite being an optical method, LIBS is not entirely non-destructive. Especially when nanosecond pulses are applied to a solid sample, a small amount of material (~pg-μg) is ablated and vaporized. Consequently, when a measurement is performed with a sample fixed in space, the spectrum may vary from shot to shot as the analyzed material is changing with time. This is particularly important when the sample is inhomogeneous.

When solids are to be analyzed, LIBS provides information about the surface in the first place. This may be a severe disadvantage when coated products need to be analyzed as the main signal will come from the coating rather than the actual product. Moreover, if the coating is a thin layer it may be destroyed.

Being around for decades, many of the disadvantages of LIBS have been studied in great detail and ways have been found to minimize or overcome them. This includes experimental aspects, data treatment, and data evaluation.

Conclusion 

In conclusion, laser-induced breakdown spectroscopy (LIBS) is a versatile tool for the analysis of pharmaceutical products. It is a robust and reliable method that is available as handheld instruments as well as benchtop devices. The LIBS spectrum provides an elemental fingerprint of the sample and hence it can be utilized as a means of qualitative and quantitative analysis. Nevertheless, there are some disadvantages to keep in mind. In contrast to many other spectroscopic methods, LIBS is not a fully non-destructive method as a small amount of material is typically removed from the sample during the measurement. On the other hand, the potentially high repetition rate can allow a rapid elemental mapping, e.g. of the surface of a tablet.

Further Reading

1. St-Onge, E. Kwong, M. Sabsabi, E.B. Vadas, Quantitative analysis of pharmaceutical products by laser-induced breakdown spectroscopy, Spectrochimica Acta B 57 (2002) 1131-1140.
2. S. Béchard, Y. Mouget, LIBS for the analysis of pharmaceutical materials. In: A. Miziolek, V. Palleschi, I. Schechter (Eds.), Laser Induced Breakdown Spectroscopy. Cambridge: Cambridge University Press (2006) 314-331.
3. B. Lal, F.-Y. Yueh, J.P. Singh, Laser Induced Breakdown Spectroscopy for Quality Control in Pharmaceuticals Industry, Journal of Optics 34 (2005) 181-192.
4. P.K. Tiwari, N.K. Rai, R. Kumar, C.G. Parigger, A.K. Rai, Atomic and Molecular Laser-Induced Breakdown Spectroscopy of Selected Pharmaceuticals, Atoms 7 (2019) 71.
5. S. Legnaioli, B. Campanella, F. Poggialini, S. Pagnotta, M.A. Harith, Z.A. Abdel-Salamb, V. Palleschi, Industrial applications of laser-induced breakdown spectroscopy: a review, Analytical Methods 12 (2020) 1014-1029.

Author biography

Prof. Dr. Johannes Kiefer is Chair Professor and Head of the Engineering Thermodynamics department at the University of Bremen, Germany. In addition, 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.

Subscribe to our e-Newsletters
Stay up to date with the latest news, articles, and events. Plus, get special offers
from American Pharmaceutical Review – all delivered right to your inbox! Sign up now!