John Coates

, John Coates (1) described a miniaturized spectral sensing concept based upon a spectral engine. In that column, the idea of a miniaturized platform for spectral measurements was developed. It discussed how miniaturization can enable analysts to bring the measurement system to the sample, rather than vice versa. The focus was on development of in-line and on-line measurement systems for continuous monitoring. The topics covered were beyond the traditional process analytical applications and included unconventional thinking on in-line water measurements for environmental monitoring and public safety applications, applications in the wine and brewing industries, and medical and life science applications. They involved the fabrication of low-cost components as either a true spectrometer or spectral sensor on a chip. In volume, like all chip-based technologies, the cost of such devices can drop to a point where spectral measurements can be entertained in consumer applications and consumer-based products. 

In this column, the theme is expanded to include handheld measurements using a palm-sized device. This device provides the full spectral capability discussed in the earlier article, but with a slant toward making common analytical measurements at a personal level. It is a truly portable system functioning as a spectrometer and can be used either open ended or as a dedicated analyzer. As an analyzer, it can make use of "canned" standard methods that are available as Internet downloads or it can run user-developed methods. A method is defined as a recipe for measurement of a specific chemistry or a material property from a natural or induced chromophore (role of a reagent) and from the resultant spectral data followed by the necessary data conditioning and calculations. Another key element of any spectral analysis is how the sample is handled and optically interfaced to the system. The device in this column brings everything together in a single unit, where a complete analysis can be performed by a single-handed operation. 

Emil W. Ciurczak is chief technical officer at Cadrai Technology Group (Bel Air, MD). He can be reached via e-mail at:  emil@ciurczak.com			

This column provides readers with an insight into how it is best to consider the development of instrumentation on a platform basis. By definition, platforms (such as the infamous IBM PC) are flexible, easy to customize, and can be applied to multiple applications — some previously not considered for spectroscopic analysis. The platform discussed leads into an affordable palm-sized measurement system. The hope is that readers will be encouraged to think beyond the traditional limits of spectroscopy; also, another byproduct of this thinking is to introduce a concept that will open doors into the educational system and into the home or consumer market. 

By education and training, this author is an analytical chemist with a background in analytical methods development and use of instrumentation. Early involvements with computers (back in the mid-1960s) led to the expansion of applications by the processing of spectral data for material characterization and automated methods of analysis. Since the mid-1970s, the focus has expanded further to include the development and design of instrumentation and sensors. Drawing on all these experiences and skill requirements, the author has fulfilled some of his ambitions to develop a miniaturized spectral measurement system that is automated, easy to use, and readily customizable to meet the needs of a broad range of chemical, physical, and life science–based measurements. 

The thought processes involved are reviewed here. The first consideration is the sample. For years, discussions have been going back and forth about what should come first, the instrument or the sample. Traditionally, the instrument is designed first and the sample handling is fitted in somewhere, either in a sample compartment or an extension of a sample compartment: some interface that is generated by "light pipes" or optical fibers. In all cases, the sample optical interface might be a compromise relative to light-coupling efficiency and convenience of use. In the current system under consideration, the sample and its method of introduction and optical interfacing were examined first, and the instrument was designed to interface with the sampling device. 

The sample is drawn with a pipette-style assembly into a measuring chamber that has a retroreflective format. This enables convenient one-sided sample illumination, reducing the net physical pathlength. A 5–50 mm pathlength range is considered to be optimum for most visible and near infrared (NIR) measurements. Consideration for shorter pathlengths has been given for more optically dense media and will be implemented with time for applications in which dilution of the sample is undesirable. 

The sample interface is designed for easy removal of the sample components and is produced from low-cost materials, making them disposable. The physical interface between the sample chamber and the spectral sensor is accomplished with nonconventional optics in which light guides, shrouded by a black absorbing material, generate a pseudocollimated light path.  

Traditionally, scientific instruments evolved from benchtop boxes with a collection of control knobs, buttons, lights, and displays to relatively simple-looking boxes that are controlled via a personal computer. This is a good-news, bad-news scenario in some respects because using software to drive an instrument requires learning a user interface and understanding the interactions involved in different functions of the software. With modern Windows-based graphical user interfaces, this interaction has been simplified to some extent. The current generation of instrument users has grown up with this style of interface (while a few of us old-timers recall the simplicity of pushing a scan button). The very latest generation is more familiar with simple menu-driven pushbutton devices, such as used on a modern cell phone or an MP3 player. In designing a palm-sized device, one can think about these simple user interfaces, or the more complex interfaces of the modern smart phones, such as the Palm Treo (Palm, Inc., Sunnyvale, California) or the BlackBerry (RIM, Waterloo, Ontario, Canada). Going this latter route can result in a crowded and inconvenient user interface. 

In the design of the current handheld device, a different philosophy was adopted, based on a hybrid approach. There can be many reasons why a spectrum is acquired or a handheld device is used to make an analysis. Spectra can be recorded to perform some form of comparison in which a visual interface to the spectrum is desirable. In such cases the interface of a handheld device has limited capability, and so an ability to upload the spectral data and to view the spectrum or perform data manipulations is important. For this type of operation, a simple set of operations to scan and store a spectrum is all that is required, and a simple push-button interface that activates a prescribed procedure is all that is necessary. Alternatively, as a true handheld analyzer, there is a need to select a predefined method that combines a set of operations from spectrum acquisition to the computation of a final result. The advantage of a true spectral sensor at this point is that many different methods can be performed by a single instrument, and one is not constrained to a limited set of wavelengths for a given measurement. In this scenario, the user interface is required to permit selection of the appropriate method, an operation that can call on the MP3 player approach. The final computed result can be displayed, in numerical or alphabetic form, on the same display used for the method selection. 

Many of the traditional handheld analyzers offer multiple methods of analysis when the analyzer is obtained for a specific set of analyses. A common example here is the range of analyzer products offered for water analysis. Some of the more basic devices might offer a limited set of common analyses, while more sophisticated systems might offer up to 100 stored methods. Almost without exception, the methods used are related to the use of specific reagents and are manifestations of published standard methods, such as the USEPA methods used for water analysis. Such systems are very popular and serve an important role. In terms of how the methods are implemented, most are based upon a single measurement point, usually a wavelength that defines an absorption maximum, and one, or possibly two, reference (or baseline) points. Such an approach follows a simple Beer's law approach to the data evaluation in which the net absorption for the sample is compared with a standard calibration, which can be defined in terms of a coefficient (slope) and an intercept. 

If the handheld device is designed to function as a spectrometer rather than a simple photometric measurement system, then one can perform any or all of the standard methods, whether they be for water analysis or any other predefined method. In addition, one can entertain other types of measurement in which more sophisticated methods of data extraction and manipulation can be performed. For example, data extraction involving functions other than simple peak position or height can be considered, such as peak area and derivative calculations. Once the critical spectral data are obtained, calibrations involving nonlinear functions, more than one analyte, or regression-based quantitative methods can be implemented. Finally, for some analyses, a 1:1 comparison to one or more stored standards might be a requirement, as in some quality control applications. Setting up such approaches normally requires a PC-based system for the development of the method, but once developed, the method can be offloaded into the handheld device for standalone operation. When the method is executed, it might outwardly appear as any other standard method, but within the system, full data-array-based operations are performed, yielding a result or a set of results.  

In the manner described, the handheld spectral analyzer can offer similar functionality to standard handheld analyzers that perform standard methods. These can be made available as standard stock methods. However, with the degree of customization, the same device can be transformed into an analyzer or a comparator (spectral comparisons) for a host of other applications. Such applications can be made available, again in the form of stock methods, or as a user-configurable system. In essence, this approach provides a flexible tool that one day might be a water analyzer, and another day might be an olive oil analyzer. 

To this point, the spectral range has been assumed to be in the visible, operating from 400 nm to 700 nm. A system operating in this range is not limited to absorption, and with some minor reconfiguration of the optical interface and a different configuration of the sample handling system, it is possible to consider the spectral sensing system for certain fluorescence-based applications.  

Several options are available here, depending upon the light (excitation) source and the configuration of the detection system. Such a measurement system can service a wide range of applications involving different fluorophores, many popular for life science and forensic applications. Furthermore, the same type of sensor construction can be constructed for the NIR, in the region from 700 nm to 1100 nm. While this region is not as commonly used as the longer wavelength spectral regions, it can service a wide range of fluid-based applications featuring mixtures of organic compounds or water-based solutions. A common example is the measurement of the alcohol and sugar content of wines, as featured in the earlier article.  

The Platform Concept — Transforming Ideas into Reality

The system described here is a prototype of a fully functional system to be introduced at Pittcon 2007. The data shown here are very preliminary, and are not indicative of the final quality or performance of the sensor. They are intended to demonstrate the ability of the system to generate a recognizable and workable spectrum, and they were produced on a functional system. 

Some systematic noise is present in some of the data, as illustrated, especially at the higher absorption regions of the spectral data. The source of this noise has been identified and will not be present in a final system. It is important to recognize that the data presented were obtained as a single capture from the array, a process that took approximately 3 ms. In the final system, it is expected that the data acquisition time could be shortened to a tenth of this value, approximately 300 μs — essentially a real-time measurement. However, in a handheld device, such speed is seldom a requirement, but it is nice to know that the speed is available. 

The product series will be called the i-Lab, from "individual laboratory instrument." The approach is to place the power of a laboratory instrument in the user's hand. The background to the approach is highlighted above, along with the philosophy for use and operation. Figure 1 provides a view of the series for 2007, with the visible (green), NIR (red), and fluorescence (lilac) models being illustrated. As illustrated, each unit is fully self-contained, and includes the disposable sampling head on the top of each. The tips themselves are also removable and the lengths are selectable. The part located on top of the unit is the removable "cell" unit, which is a retroreflective module that will provide optical pathlengths ranging initially from 5 mm to 50 mm.  

Figure 1: A new integrated spectral measurement system; palm-sized spectral sensor with sample transport.			

An initial functional prototype, with a rough prototyping of the sampler system, is shown in Figure 2. The unit is designed for singlehanded operation (either left or right), and this includes filling and emptying with the bellows, the use of the controls, and the ejection of the sampler following the completion of an analytical cycle. With the anticipation that the system will be used for field applications, the body has a rugged and waterproof construction, with a rubber overmolded grip. When used standalone, the system is powered by three AA batteries, which are estimated to last for several months before needing replacement. When used in a laboratory or office environment, the system can be operated tethered by connection to a PC via the USB interface. When used in this mode, power is supplied via the USB cable. 

Figure 2: An operation prototype of the handheld spectral sensor.			

A clear and easy-to-navigate user interface is important, and while the temptation is to include some form of keyboard, for standalone operations, this is not considered to be so important. A simple up and down arrow approach to option and method selection has been implemented. Examples of the user interface are provided in Figures 3 and 4, where the white backlight LCD is illustrated with operational instructions. In the case of the measurement cycle, this includes the acquisition of the dark current, the spectral background, and the final sample data acquisition. The speed of data acquisition is sufficiently fast for the visible spectrum (the NIR will take longer) that the entire average measurement cycle should not take any longer than a second or so. 

Figure 3: Simplifying the user interface of the spectral sensors.			

Figure 4: Making a measurement, from loading the sample to taking the measurement.			

The example spectra shown in Figures 5–9 are illustrative of the nature of the final form of the spectral data, as acquired and as transferred back to a laboratory-, office-, or home-based PC. In terms of raw specifications, the final signal-to-noise specifications are undetermined at this time. For now, the presence of a low level systematic noise (to be removed) artificially reduces that value. The spectral resolution is in the range of 8 nm (average) for the visible system, and in the order of 11 nm for the NIR system. The photometric range for now is specified as 0–1.5 A, but it is expected to be closer to 0–2.0 A for the final systems. Currently, a 16 A/D range is in use, providing a digital count of up to 65,000 for the raw intensity measurements. Examples of intensity readouts are provided for single red and green LEDs, in Figure 5, and for a white LED, the main broadband light source, in Figure 6. 

Figure 5: Spectral responses from LED light sources.			

Figure 6: Broadband solid-state light source.			

The spectral data shown in Figures 7–9 are illustrative of typical color-based measurements and of the role played by the system when collecting full spectral data. These data were collected using the single white LED light source shown in Figure 6. This source has relatively low output at the extremes of the wavelength range (400–450 nm and 650–700 nm) and is responsible for amplifying the systematic noise component referenced earlier. In the final form, the system will feature a composite light source consisting of the white LED combined with selected individual LEDs that will boost output in the regions of low output. Optimizing software will level the outputs of the composite LED. The benefits of using LEDs as light sources are obvious in terms of ruggedness, lifetime, and low power consumption. Bearing this in mind, a composite LED source also will be used for the NIR version of the system. 

Figure 7: Adaptation to standard measurement methods; example, residual chlorine in drinking water.			

At the time of introduction, the system will be complete in its most basic form, as described here. Future enhancements, due to be completed later in 2007, will include a graphical display of spectra on the built-in LCD (the LCD is bitmap addressable), a wireless interface, and GPS. The process version described in the earlier publication (1), for continuous monitoring, will be available in late 2007 or early 2008, and in its basic form it will use a CAN Bus interface and will be produced also (with the help of a third party) in an intrinsically safe (IS) package. 

Figure 8: Continuous spectral data enabling multicomponent analysis.			

Applications of a Handheld Spectral Sensor

The range of applications of an analytical instrument that fits in the palm of your hand is very large, especially when the system includes the sample and data handling. Taking these considerations into account, and with out-of-the-box thinking, such a system can now be considered for many applications that would not be practical based upon features (or lack of) or cost. Three simple applications are shown in Figures 7–9. 

Figure 9: Property measurements: the measurement of pH.			

It is expected that the system will have appeal for water monitoring applications, from the water source (stream, river, lake, reservoir, or well), to water purification, to the public water distribution system (public safety), through to the incoming water supply in public buildings, offices, and the home. Also, there are many intermediate considerations for water analysis, including industrial process water, water used in cooling systems, and industrial runoff and effluent control. From an analyte perspective, this can include traditional methods, such as the measurement of residual chlorine in drinking water (Figure 7), methods for runoff of fertilizers and other ground contaminants (nitrate, phosphate, ammonia), heavy metals (lead, mercury, copper, chromium [VI]), as well as biological materials and toxins. In the latter case, methodologies that use the fluorescence detection version of the system will be put in place. 

When one uses a full spectrum approach to a measurement, there is a wide range of possibilities of how the system can be used. Many natural and artificially induced colors can exist in a wide variety of chemical systems. Many times, a number of these coexist. Figure 8 is a simple illustration with some simple dyes. A green dye is mixed with a red dye. The green dye in itself is a composite of blue (λ

 ~460 nm) dyes. The composite spectrum of all three dyes is shown as well as the computed difference spectrum showing the isolated red component, itself with a multiplet structure, with the primary λ

 ~525 nm. The message here is that complex systems can be represented and analyzed. The integrated software (as well as the PC-based software) is intended to provide access to the data from such complex chemical systems, and full multicomponent capability will be available. 

This latter statement is important because it opens the door to evaluating a broad range of natural products, such as olive oils and other natural color food products, to manufactured products that contain multiple ingredients, each with their own spectral contributions. As noted earlier, this is not restricted to the visible region, and the NIR-based system will provide extended coverage to include noncolored ingredients. In some processes, one might want to study a changing equilibrium, where an ingredient changes from one state to another, and where distinct chromophores are present for initial, intermediate, and final states. An acid-base indicator is a good example of this: many natural products exhibit such changes in color. Optical measurement in pH is not a new idea, but it is particularly easy when one has full access to the spectrum. In the case illustrated (Figure 9), an aquarium testing indicator is studied from the nominal neutral (which is around a pH of 6.8 in this case) to the extremes of free acid (λ

 ~600 nm). With calibration of intermediate values, the fine control of pH balance around the neutral value can be accurately determined and monitored. Traditional pH electrodes do not function well at the extremes of the pH range (or in nonaqueous media). However, the spectral measurement system as illustrated can be calibrated to handle the extreme ranges, as well as certain nonaqueous situations. 

A handheld measurement system is not anything new. In fact, handheld analyzers, based upon optical spectral measurements, have been around for decades. Measurement systems have existed for a long time now for water quality measurements, for the safety of swimming pool water, and for clinical and personal health measurement systems, to name just a few. What this article is about is a paradigm shift. Yes, this is a horribly overworked cliché, but once in a while it has actual meaning. That is what is intended here. The message is that if one focuses on a platform concept, rather than a specific instrument type or a specific end application or market, one can end up with a power tool that can be applied to numerous applications. This is particularly the case if you can place the tool in the palm of your hand, and if buying the tool does not break the bank. 

The latter point is extremely important because it influences directly the scope and magnitude of the final end-user market. As a sidebar, the concept discussed in this column has been in the mind of this author for more than a decade. What is critical when developing a technology is obtaining sufficient funding to enable the concept to be developed and eventually demonstrated. Unfortunately, in this post-1990s era, it is next to impossible to gain funding for a concept. Analogies are important, and one has to wonder if Steve Jobs or Bill Gates would have succeeded if they went to get technology investment today. When you think about it, the question always is "What's the Market?" and "How many are you going to sell? and "How quickly?" Both Jobs and Gates developed platforms; both are visionaries. Imagine them saying this technology will eventually replace music records and this operating system will be on mobile telephones. This approach does not work in today's technology investment market. 

In no way is this discussion meant to imply that the handheld spectral sensor covered in this article is in the same league as a credit card–sized MP3-type music player or the Windows operating system. However, like these two systems, the spectral sensor features important enabling technology and both are designed around a platform concept. Like a personal computer, this spectrometer platform is scalable. If one thinks out of the box, and one considers how powerful spectroscopy can be for solving a broad range of modern applications, this platform approach has significant potential. 

The platform discussed provides a full spectral measurement system in a convenient package and at a price that fits most people's pockets. This is important because now everyone in a laboratory can have their own personal spectrometer, field workers can perform important analyses without the need to send samples back to the laboratory, and it is now possible to consider doing spectroscopy in the classroom. This point is very important because today we find fewer people being involved in spectroscopy. However, if one can integrate spectroscopy conveniently and cost effectively into a school's science curriculum, then there is a chance that we can stimulate the interest in spectroscopy at an early age. For example, in a fifth-grade science lesson, there are many measurements that can be made to illustrate the science (whether it be physics, biology, or chemistry) and to introduce young people to sensors and instrumentation. 

This column has gone one step further than the original column (1) by introducing the spectral engine–based platform concept into a practical measurement system. One of the messages in the original article was taking the measurement to the sample, rather than the norm. Unlike common handheld analyzers, this approach provides a fully operable spectral measurement device. The system can be configured as an analyzer, but instead of being a rigidly fixed device, the system is user configurable. That is the benefit of having an open-ended spectrometer. As an analyzer, the system is fully portable; however, as a spectrometer, the device can be connected to a PC and can have the flexibility of a traditional laboratory instrument. Methods can be developed and tested on the PC and can be downloaded to the handheld device. In the opposite direction, spectra can be measured and uploaded to a fully configured spectral manipulation package. 

Currently, as covered in this column, the spectral sensor operates in the visible spectral region from 400 nm to 700 nm. In the current configuration, the platform is adapted toward liquids, where the sample is drawn into a disposable sampler. Future configurations will include a dipping interface (expanding the concept of the smart stirrer) and a surface measurement version for liquids, pastes, and solids. From a configuration point-of-view, a fluorescence-based system is not so different from a Raman system, and many of the performance requirements are similar. With this in mind, an expansion into Raman is also under consideration. 

Articles

Guest author John Coates describes handheld measurements performed using a palm-sized device that can be used either as an open-ended spectrometer or as a dedicated analyzer.

Think Small Revisited: Handheld Spectroscopy

Greetings, seekers of new spectroscopic "toys." As is my wont, I try to discover new gadgets in the fields of molecular spectroscopy. Fortunately, I know — pretty much — who is working on things that fit my criteria for "great" (smaller, faster, and wireless). The last criterion can be substituted with "portable." Thus, I can pester these folks for articles for this space. This month, in time for PittCon, I have a sweet piece by my friend, John Coates (Coates Consulting, Newtown, CT) about a nifty, handheld Raman instrument. Eventually, I will present several of John's innovations, but this is the first he wished to share. Enjoy!

This is the first in a series of three articles I will contribute to this column that will discuss the emergence of new instrumentation technologies expected to impact the role of spectroscopy outside of the boundaries of the laboratory. In this article, a new concept for Raman spectroscopy will be reviewed as it pertains to process analytical technologies (PAT) and other industrial applications. While the technology crash at the start this decade did much damage to the economy of this country (and to our personal savings), it did spawn new concepts of measurement that are surfacing now. These are providing excellent opportunities for new spectroscopic applications.  

The telecommunications industry is one of the industries that nosedived, but since has offered up new products and technologies. Four major attributes come from this telecom heritage — miniaturization, ruggedness, advanced optical concepts, and the potential for low-cost production. These attributes meet many of the needs for PAT, and represent an opportunity to change the way that instrumentation is viewed and implemented. This is a move away from the traditional instrument and towards the spectral sensor. Next stop . . . the fabled Star Trek Tricorder? 

Raman Spectroscopy as a Process Analytical Tool

The period between 1967 and 1972 was a landmark time in modern spectroscopy. Within that window of time there were critical advances in vibrational spectroscopy, with FT-IR and "Laser Raman" spectroscopy at the top of the list. At that time, the two techniques were to take over from the status quo — or at least that was the belief. Eventually, in the 1980s, FT-IR did become the de facto standard for infrared spectroscopy. Raman spectroscopy promised to be a leading technique, offering unique opportunities for micro sampling, work in aqueous solutions, and simplified optics, based upon the use of glass, rather than the exotic materials required in mid-infrared spectroscopy (mid-IR). There is no doubt that Raman has found a strong place in today's analytical chemistry arsenal. Also, there are some significant and unique opportunities for the technique. But, until recently, it was difficult to view it within the context of modern day IR spectroscopy.  

Mid-IR has become a cost-effective, pushbutton technique in the laboratory, being used for a wide range of applications. The desire has been to try to get Raman to be of equivalent status. The system covered in this article has the opportunity to fulfill this desire. It is a compact, easy-to-use device with push-button operation. Additional advantages over its infrared spectroscopy counterpart are that it is completely portable and does not require any special sample-handling accessories. 

Today's Raman systems feature low-power near infrared (NIR) lasers, operating with a few hundred mW of power. The NIR wavelength of incident light reduces the occurrence of fluorescence and the lower power aids laser safety. The key to improved performance of modern instruments is, in part, due to improved photon management. The handheld analyzer covered in this article (Ahura Corp., Wilmington, MA) is an example of optimized light management, by providing a simple-to-use sample interface, with minimal issues relative to laser safety.  

This instrument provides three pre-defined levels of laser power output: 50, 150, and 300 mW. Two simple approaches to sample handling are provided: one with sample cavity designed to accept glass sample vials, and the other in the form of a sample "proboscis" in which the laser is focused just beyond the tip of the "proboscis-style" probe. This instrument, currently marketed for hazmat and homeland security applications, is known as the Defender. To meet the needs of these applications, the analyzer has been designed to meet military specifications in terms of performance, reliability, and ruggedness. 

The primary application (at this time) is for the characterization and identification of dangerous chemicals, usually in their containers, with a highly simplified user–operator interface. While these specifications clearly meet the needs of the original application, anyone familiar with plant-based operations will recognize that they also are ideal for a wide range of plant and manufacturing applications. The concept of a handheld instrument that can survive the 6-ft drop test and can provide detailed spectral analysis at the push of a button should be enough to make it popular with any plant manager or technician. 

This Raman analyzer is completely self-contained, operating on battery power (small lithium ion rechargeable cell), and housed within a rugged and sealed enclosure. The unit is constructed with a stabilized 785-nm (NIR) solid-state laser source, an integrated imaging module, and a 2048-pixel diode-array-based spectrograph. All electronics, including a single-board processor, also are fully integrated. As noted, the user interface is a simple set of push-button controls linked to a menu-driven color liquid crystal display, as shown in Figure 1. A sophisticated chemometrics-based spectral search package is included that provides positive identification for discrete compounds and calculated compositions for materials identified as mixtures. The success of the identification is dependent upon the compound in question being in the stored database. If the material is identified as a mixture, then an attempt is made to identify the components, based upon their contributions to the Raman spectrum (from the pure component spectrum), and to indicate the percentage composition, as indicated in Figure 1.  

Figure 1. The Ahura handheld Raman system illustrated with the simple menu-driven user interface.			

The system described originally was designed for a demanding and hazardous application. Meeting the requirements of this application ensures that the system is well-matched to demands of applications related to process analytical and product quality control. Raw material screening in warehouses and production areas is a broad-based application for many industries, from pharmaceuticals to consumer and food-based production. A major benefit of the technique is the ability to characterize materials within the original container, as illustrated in Figure 2.  

Figure 2. Convenient sample handling for material identification with sample container.			

It is not difficult to envisage a variety of plant-based applications for the analyzer in its current form, from this example of materials screening, to the at-line analysis of production samples, to the characterization of spills and residues found within a plant or factory environment. In this last example, an important application is for the screening of effluent and waste materials from all forms of manufacturing plants, including those which are not traditional candidates for process analytical chemistry, such as metals manufacturing and metal treatment plants. The current format of the analyzer is ideal for plant applications, insofar as the user interface is simple, and the packaging is rugged, and has the potential to meet the requirements for operation in hazardous (flammable) environments. The analyzer currently is undergoing tests to evaluate its suitability for operation in environments that are defined by the National Fire Protection Association (NFPA) standards. The analyzer is a low-voltage device, and with its compact design it is anticipated that the current package will meet Class 1, Division 1, or Division 2 safety requirements.  

Benefits of Raman for QC and Process Monitoring Applications

During the past decade, we have seen an increase in the use of Raman spectroscopy for process analytical applications, including some lab-based QC applications. In the traditional sense, Raman spectroscopy offers a number of advantages over other forms of vibration spectroscopy for "real-world" process and QC applications. These include the ability to operate in a glass-based environment, in which the sample can be monitored through a container or reaction vessel wall or through glass piping. This can minimize sampling requirements, and in some cases can eliminate the need for emersion probes, the latter making the monitoring nonintrusive and also eliminating the risk of probe fouling. In the case of the Raman system in question, the imaging can be optimized to be just beyond the glass surface.  

Another benefit of Raman is the ability to monitor water-based solutions. Water is a weak Raman scatterer and as a result, it has a relatively weak contribution to the spectrum of water-based solutions. This is contrary to the limitations imposed on IR and NIR measurements. Many compounded products used for pharmaceutical and consumer-based applications are water-based, or contain similar solvents to water, and so a Raman-based system is ideal for inspection or production monitoring applications with such media. 

If we review the information content of the Raman spectrum, we find that it can be as informative as the mid-IR spectrum, especially for materials characterization. The following is very much a generalization, but it does serve to define Raman as a qualitative and quantitative tool for process analytical chemistry. Both mid-IR and Raman have highly detailed spectra with a high redundancy in information content. At first sight, the IR spectrum is dominated by vibrations from polar functional groups, and skeletal vibrations linked to C–H and C–C vibrations. Raman is similar, and the spectrum also contains information related to C–H and C–C vibrations, and in general is dominated strongly by skeletal vibrations. Vibrations from polar groups, such as the C=O carbonyl group, tend to be relatively weak in the Raman spectrum, whereas polarizable groups, such as S–S, C–S, and C=C, which generally are weak in the mid-IR, do provide strong Raman signatures. 

Skeletal vibrations are very much dependent upon the structure of individual molecules and, as such, Raman spectra tend to be highly individualistic in nature, whereas vibrations from characteristic functional groups are more systematic in nature, and as such are easier to characterize. Characteristic functional group vibrations are very dominant in the IR spectrum. Thus, spectral interpretation, in terms of the identification of fundamental functional groups and molecular structures, is relatively easy from the IR spectrum. As a result, families of compounds are recognized readily from repetitive signatures in their IR spectra. While some first-principles interpretation is possible from the Raman spectrum, it does tend to be compound dependent, and the contributions from the molecular backbone are often the most dominant.  

For normal condensed-phase compounds, many of the characteristic frequencies from functional groups are observed in both IR and Raman spectra. Differences arise in intensity and it is common that a vibration that is strong in the IR spectrum is weak in Raman and vice versa. A good example is provided in Figure 3 by comparison of the spectra of vegetable oils, recorded directly in glass vials from the handheld system. These materials contain both an ester carbonyl group and at least one free double bond, normally with a cis configuration. In the infrared, the carbonyl centered around 1745 cm

  is the most dominant band, and often the strongest band in the spectrum.  

Figure 3. Comparison of the C=O (1745 cm-1) and C=C (1660â1650 cm-1) stretching vibrations for common vegetable oils.			

As noted, the opposite situation occurs in the Raman spectrum, with the double-bond stretching vibration, located between 1660 and 1650 cm

 , being one of the most intense bands in the spectrum. This is a very useful measurement because the characteristics and the functionality of these oils often are defined by the double-bond content (often measured chemically as an iodine value); the Raman spectrum provides a direct measure of these properties. 

Essential oils are important as flavor and fragrance components. These compounds are differentiated in terms of chain branching and double bonds, as well as the presence of key function groups such as ketones, aldehydes, esters, ethers, and alcohols. It is very common to have multiple methyl groups on the same carbon atom with these compounds; Raman spectroscopy is a very sensitive tool for the detection of such structural arrangements. Figure 4 provides a comparison between α-pinene, a major component of pine oil, and eucalyptol (1,8-cineole), a component of eucalyptus oil. The latter is a component of common therapeutic ointment rubs. Both compounds have a gem-dimethyl arrangement with two methyl groups located on a single ring carbon atom. The intense band between 650 cm

  most likely is assigned to the symmetrical stretching of the methyl-carbon bonds for this grouping. Note that both spectra are uncorrected for detector response, and so the intensities of the higher frequency (wavenumber) bands are attenuated relative to their actual response. Both compounds provide rich spectra that are represented uniquely in the Raman, indicating further the ability of the portable Raman instrument to provide reliable material characterization.  

Figure 4. Characteristic skeletal vibrations for common essential oil ingredients.			

The following are examples of solid-phase spectra, directly recorded from either the powdered or tableted forms of the materials concerned. In terms of unique characterization, the spectra of simple sugars (α-D-glucose, D-mannitol and D-sorbitol) and related compounds (ascorbic acid) are presented in Figure 5. The infrared spectra of these compounds are dominated by hydroxy (R–O–H) and (C–O–H), and ether (C–O–R) vibrations, and many such compounds appear very similar in the mid-IR. In the Raman spectrum, there is very little evidence of the hydroxy and ether vibrations, and the spectra are all different and highly differentiated as a function of their structures.  

Figure 5. Raman spectra from powdered sugars and related compounds.			

Many of these sugars are important in food and common pharmaceutical products, often used as excipients. Finally, while on the subject of formulated pharmaceutical products (dosage forms), the spectra of three common analgesics are presented in Figure 6. While they have been labeled as the active ingredient, there has been no attempt to separate them from any excipients. Such spectral data can represent the fully formulated products, and it is possible to quantify the ingredients, when the spectral data are available for the individual key ingredients. An example of such an analysis is provided on the display in Figure 1 for a compounded APC tablet. In this example, the concentrations were computed by calculating the contributions of the individual compounds to the overall recorded Raman spectrum.  

Figure 6. Raman spectra from common analgesic tablets.			

This article has highlighted the operation and performance of a portable Raman system that originally was designed for a single purpose — for the identification and characterization of hazardous materials. In producing such an instrument platform, the manufacturer had to pay careful attention to key design criteria such as reliability, speed of operation, simplicity of operation, and reliability. While these are obvious key criteria for the application at hand — the identification of unknown toxic substances in spills or unmarked containers — they also are the criteria important for production and plant-based applications. With the current instrumentation focus on PAT, the portable Raman analyzer offers a host of application opportunities in the pharmaceutical industry, from raw material screening to the inspection of fully packaged dosage forms. In both cases, the analyzer can measure the material without special sample preparation, non-invasively, and if necessary, unwrapped in the original container or packaging.  

Raman is a powerful technique for material identification and characterization. Although not addressed directly in the portable analyzer, it also can be used for quantitative measurements. Currently, the analyzer works stand-alone and spectral data are stored on a removable compact flash card. One can be certain that a means for wireless communication is not far behind. As indicated earlier, one more step towards the Tricorder. 

Guest author John Coates describes a new, compact handheld Raman instrument.

Author | John Coates

Articles

Think Small Revisited: Handheld Spectroscopy

New Technologies for Process Analytical and Quality Control Applications: Compact Raman