Laser-induced Breakdown Spectroscopy: the Elemental Facts

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By Louis St-Onge, PhD

Imagine you could capture some harmless light given off by an ordinary light bulb and store it in a box. Now, imagine taking this light and sending all of it almost instantly (in about ten-billionths of a second) along a narrow beam. You would have something like a pulsed laser beam — concentrated light. Under these conditions, light is not just there for lighting. It can burn stuff; it can break matter down to pieces, literally to atoms . . .

The Sun in a Box

Children are often fascinated (with reason) by the potency of the sun when combined with a simple object like a magnifying glass. Something as immaterial as sunlight can actually, at a distance, poke a hole in a sheet of paper, without you having to touch it. Take a pulsed laser beam, and you will get the same result. Not only will you be able to mark the surface of your target, but also produce above it a flame of some sort — more exactly, a hot ionized gas called plasma, which resembles an electrical spark. This not only applies to paper but also to all sorts of materials in all states of matter: metals, rocks, organic powders, liquids, even gases.

Imagine that when burning paper with your magnifying glass you could look carefully at the flame and know right away exactly what the paper is made of. This is what laser-induced breakdown spectroscopy (LIBS) is all about: focusing a pulsed laser beam on a target, which transforms a small fragment of its surface (approximately 1/2 mm in diameter) into a hot and luminous plasma, and carefully analyses the different “colours” that compose the light it gives off (Fig. 1). This latter technique, known as optical emission spectroscopy, can tell you what atomic elements the target is made of, and their respective concentration in the target.

The Light Touch

Around the time when the laser had just been invented (c. 1960), someone decided to produce a spark with it and scrutinize its optical emission. Laser-induced breakdown spectroscopy, also known as laser-induced plasma spectroscopy, is therefore about as old as the laser itself. Only in the last 10 years, however, has this technique emerged as a powerful analytical tool, mainly because more rugged lasers and high-performance multichannel photodetectors became available.

With LIBS, only photons are at work: sampling of the target surface occurs because of the focused laser light, and all information on the sample composition is carried by light emanating from the plasma. In other words, analysis can be carried out even behind a window. Only access to light is required, without physical contact with the sample. This feature of LIBS is very useful when one needs to carry out analyses during industrial processes in harsh environments (e.g., nuclear power plants, mineral smelters, coal-fired facilities, etc.). Analysis can also be conducted at a distance, which for instance has spurred the development of LIBS technologies for standoff analysis of the Martian soil.

Another appeal of LIBS is that materials can be analysed as they are, with little or no preparation. In particular, it is not required to put solid samples in liquid form as is the case with several other analytical techniques. Combined with the fact that the analysis itself is very fast — it generally takes less than a minute to obtain a precise measurement — LIBS is much less time-consuming than most conventional techniques.

A Different Road

In terms of analytical performance, LIBS has come a long way in recent decades. The precision of the analysis is now comparable to other techniques. And for most elements of the periodic table (including light elements), atoms in the parts-per-million range can be detected. This is sufficient for many applications found in industry but, admittedly, does not rival established laboratory techniques, some of which can reach the parts-per-billion range or below.

But the intention with LIBS is not necessarily to replace existing laboratory techniques. With LIBS, instead of taking a sample out of a process stream and bringing it to the lab, one can travel a different road: bringing the “lab” to the process line for in situ, real-time analysis.

At the Industrial Materials Institute (IMI) (Boucherville, QC) of the National Research Council of Canada (NRC), research into the application of LIBS for process monitoring was initiated in 1992, with Mohamad Sabsabi, PhD as a key developer. Since then, the LIBS team at IMI has grown in size and evolved to be one of the world’s most active in this field, bringing fundamental improvements to the LIBS technique (many being patented). It has also successfully carried out field studies in industry and developed prototype instruments for process monitoring. In 2001, the IMI installed a LIBS system at an industrial plant for continuously monitoring the composition of a liquid process stream. This sensor has flawlessly operated 24 hours per day, seven days per week, for over two years, at a rate of one measurement per minute, and has completely replaced previous analytical practice.

In addition to several applications in the mining and metallurgical sectors, as well as work on more specialized materials (e.g., for aeronautics), the NRC has pioneered applications of LIBS in the life sciences, including recent work on the detection of various elements in biological fluids. The main contribution of the NRC in this field, however, has concerned the analysis of pharmaceutical materials, including solid dosage forms (such as tablets) and liquid formulations.

Based on promising early work in collaboration with Merck Frosst Canada & Co. (Kirkland, QC), IMI has catalyzed the creation of a spinoff instrumentation company dedicated to providing the pharmaceutical industry with novel analytical tools based on LIBS. This company, Pharma Laser Inc. (Boucherville, QC), was founded in 1997. Following an R&D and beta-testing phase, Pharma Laser is now offering a commercial LIBS instrument, which has sold to pharmaceutical companies in Canada and the United States. This fully automated instrument has been designed to support pharmaceutical R&D and, more importantly, to be used on the production floor for the unattended at-line analysis of up to 26 tablet samples/analysis (Fig. 2), a full sample set taking only on the order of 15 minutes to analyse. At the moment, the instrument is mainly used in an R&D environment for formulation development and process optimization.

Atoms as Tags

But how is it that an instrument for detecting atoms can find use for the characterization of pharmaceutical formulations containing complex drug molecules? It turns out that about two-thirds of the drugs on the market contain an element in their molecular structure that is absent from the other ingredients of the tablet. Such a “tag” element (chlorine, sulphur, fluorine, etc.) therefore enables the unambiguous identification and quantitation of the drug component: the signal from chlorine, say, can be calibrated to give the drug-loading of the tablet. Interestingly, the new drugs being discovered tend to be more complex and to contain one or several tag elements, in addition to the ubiquitous elements carbon, oxygen and hydrogen. Therefore, the proportion of drug products addressable by LIBS will likely increase in the future.

The ability gained through LIBS to rapidly detect and quantitate the drug in tablets, without sample preparation, offers several opportunities: quality control, dose strength identification, evaluation of blend uniformity, process optimization and control. But LIBS can also offer something that most other analytical techniques used in the pharmaceutical industry cannot provide: spatial resolution. Indeed, the very small size of the analysis volume (the volume of starting material that is transformed into a luminous plasma) enables chemical mapping of a surface, or determination of the composition as a function of depth. In the latter case, the laser always irradiates the same spot on the sample, but each successive pulse samples a different depth as the laser gradually digs below the surface. This approach has been applied to the characterization of tablet coatings. In particular, the coating thickness can be deduced by determining how many laser pulses are required to penetrate through the coating and arrive at elements of the tablet core. By moving the sample laterally, one can thus verify the uniformity of coating thickness across the tablet.

In the tablet core itself, the active drug is mixed with other functional ingredients and filling materials, which LIBS can also evaluate. A case in point is magnesium stearate, the lubricant present in low concentrations (approx. 1%) in most tablet products. At the recent Joint Calibration & Validation Group/Therapeutic Products Directorate 2003 International Convention (CVG/TPD) held in Toronto, Ont. on Sept. 25-26, Elizabeth Kwong, PhD of Merck Frosst Canada & Co. gave a presentation highlighting the various possible uses of LIBS in pharmaceutical R&D. Among other results obtained at Merck Frosst, she showed how LIBS could be used in a simple manner to obtain the depth profile of magnesium stearate from the upper and lower faces of a tablet, relative to the tablet press.

Figure 3 shows the spectral window including the magnesium line used as tag for magnesium stearate, as well as the magnesium intensity profiles as a function of shot number. This type of information is obtainable only through LIBS. Firstly, it is spatial information. Secondly, magnesium stearate cannot even be detected using high-performance liquid chromatography (HPLC), the standard analytical technique found in pharmaceutical labs. Information on the lubricant content is usually obtained indirectly through dissolution studies. In the words of Kwong, “Sometimes dissolution tests fail and we don’t know why. LIBS is a tool that can answer such questions because it offers new information not otherwise available.”

The Future

The buzzword widely circulating at the CVG/TPD meeting was PAT, which stands for Process Analytical Technology. The new initiative surrounding the notion of PAT was described by Ajaz Hussain, PhD of the U.S. Food and Drug Administration (FDA). PAT is presented as a new philosophy for pharmaceutical process control. It is based on the observation that “quality cannot be tested into products; it should be built-in or should be by design” (from the FDA’s Draft Guidance for Industry on PAT). In other words, instead of relying on quality control of the final product emerging from the production line, sensor devices and knowledge-management tools should be included in the process loop in order to better understand each step of the process, to characterize materials at different points, and to possibly influence the process itself in real time. This new approach (at least in the pharmaceutical industry) calls for novel sensors that can be implemented in-process on the production floor.

It is clear that LIBS has all the abilities for the on-line and real-time chemical characterization of pharmaceutical ingredients and mixtures, in tablet, powder, or even liquid form. The PharmaLIBS instrument currently on the market has already been designed for at-line analysis of tablets and, as such, fits nicely into the PAT framework. It is therefore a safe bet to say that LIBS will soon make the transition from R&D to the production floor!

Louis St-Onge, PhD is a research officer with the Industrial Materials Institute (Boucherville, QC) of the National Research Council of Canada. His research interests centre mainly on industrial applications of laser-induced breakdown spectroscopy (LIBS), namely to pharmaceutical materials. He currently sits on the Editorial Advisory Board of Spectrochimica Acta Part B: Atomic Spectroscopy (Elsevier).