Anal. Chem. 2009, 81, 4623–4643
Process Analytical Chemistry Jerome Workman, Jr.,*,† Mel Koch,‡ Barry Lavine,§ and Ray Chrisman| Luminous Medical Inc., 1920 Palomar Point Way, Carlsbad, California 92008, Center for Process Analytical Chemistry (CPAC), University of Washington, Seattle, Washington 98195-1700, Department of Chemistry, Oklahoma State University, Stillwater, Oklahoma 74078, and Atodyne Technologies, L.L.C., 4699 Pontiac Trail, Ann Arbor, Michigan 48105 Review Contents Resources Consortiums Conferences Web Sites Books Workshops National Laboratories Microanalytical Systems Microelectromechanical Systems Micro Total Analytical Systems (µTAS) Microanalytical Microfluidics Microreactors Nanotechnology Biosensors Sensor Development Biological Agent Detection Chemical Detection Chemical Agent Detection Sampling and New Sampling Systems NESSI Electrochemistry or Electrophoresis Chromatography LC-MS/MS GC/MS Liquid Chromatography LC-MS-NMR LC-MS-MDF Spectroscopy UV-Visible Spectroscopy Fluorescence Imaging Infrared Spectroscopy Laser Induced Breakdown Spectroscopy (LIBS) Near-Infrared NMR Raman Spectroscopy (SERS) Surface Plasmon Resonance (SPR) Terahertz Spectroscopy X-ray Mass Spectrometry MALDI-MS Fourier Transform Ion Cyclotron Resonance-Mass Spectrometry (FTICR MS) Proton-Transfer Reaction-Mass Spectrometry (PTR-MS) Process Chemometrics Chemometrics and Multivariate Analysis Batch Modeling and Multivariate Statistical Process Control Pharmaceutical Chemometrics Pharmaceutical PAT AI or Artificial Intelligence Informatics Cheminformatics Process Control 10.1021/ac900778y CCC: $40.75 2009 American Chemical Society Published on Web 05/08/2009
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Automation of Processes and Analytical Systems Control Systems Process Control Algorithms Flow Injection Analysis (FIA) Ultrasound Miscellaneous Sensors Hand-Held Sensors Literature Cited
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This review of process analytical chemistry constitutes the eighth in a series published since 1993. This review covers the period from March 2007 through March 2009; occasionally an earlier paper of special significance is cited. The key aspects of this review include advances in measurement technologies that are applicable for real-time or process analysis. Many aspects of sensor design and development, data analysis algorithms, and process control strategies are reviewed. Process analytical chemistry (PAC) or process analytical technology (PAT) had its true origins as a specialized form of analytical chemistry some 72 years ago. Process analysis has historically been applied for problem solving related to chemical processes as well for quality control technology to determine the physical and chemical composition of the desired products in a process. Initial work with process analysis involved sampling process streams and transporting samples to quality control or central analytical service laboratories. Time delays for analytical results due to sample transport and analytical preparation steps negated the value of many analyses for purposes other than product release. Over time it was understood that real-time measurements provided timely and more useful data about a process; the real-time nature of analysis provided information for process optimization during manufacturing. The first real-time measurements in a production environment were made with modified laboratory instrumentation. Over the past 2 decades, many industrial manufacturing processes have benefited from laboratory-based process analysis technologies during manufacturing. As is generally the case for process analytical technology, new developments are related to which business areas are expanding and/or working to improve productivity. In the last several years, biobased technology has been one of the key drivers of the field as new organism based production processes have been developed and built. The other key area has been the energy/fuel industry where there has been a growing push for higher productivity. * To whom correspondence should be addressed. † Luminous Medical Inc. ‡ University of Washington. § Oklahoma State University. | Atodyne Technologies, L.L.C.
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The growth in biobased processing was mainly in the biofuels and biopharmaceutical industries and to a lesser extent, food. These areas work with a significant amount of water based processing. The water can have a significant impact on sampling and analysis as many of the PAT approaches, other than environmental analysis, had been developed for nonaqueous environments. Gas chromatography, the workhorse of traditional online analysis, is less well suited for work with water based analyses though it has been adapted for many applications in the biofuels area. In the pharmaceutical area, the often large size and polar nature of the molecules, which many times limits the use of gas phase characterization techniques, have pushed the development of new sampling and analysis approaches. The energy/fuels industry has pushed for higher productivity which has led to the adoptions and use of enabling technologies, like the New Sampling and Sensor Initiative, NeSSI. Certainly new developments have also occurred in the analyzer area for this field, but the big change has been the realization that sampling is a major maintenance cost and reason for failure of traditional systems. Development of NeSSI compatible hardware is continuing to accelerate as new sensors are now being introduced that build on the flexibility of the technology. Process analytical technology has a long history, as it is now more than some 70 years (1, 2) that it has been practiced as a way to monitor activity in a process. The early applications were used to follow the progress of chemical reactions and to gather data for problem solving purposes if the process ever went into an upset condition. As PAT has matured, the necessity of taking samples from the process has diminished. Sampling techniques and improved measurement tools have allowed for at-line and inline uses of PAT technology. Not only was taking samples and transporting to a central analytical laboratory dangerous and costly, but it also resulted in inaccurate representation of the process, as the dynamics of the process were often missed because of the time required to make the measurement. The first analytical tools that were taken to the process environment were the instruments that historically were used in the laboratory to characterize the product being produced. These gave data on the parameters of the product but often did not represent the process intermediates and process conditions, many of which could predict product quality. The types of instrumentation being implemented in PAT applications continue to involve an increasing breath of analytical tools including a wide range of spectroscopies, a number of new approaches to separation science, a growing list of mass spectrometries, acoustics, chemical imaging, light scattering, and a rapidly expanding group of chemical sensors. Developments in PAT are not limited to research in analytical chemistry laboratories, as many important advances are coming out of a variety of technical disciplines, such as engineering, biological sciences, and computer science. It is increasingly difficult for any one technical organization to follow all of the technical developments in PAT that are occurring across research operations in industry, government, and academia. This has become increasingly evident as the need for PAT in all manner of production operations has risen and the implementing organizations continue to have limited resources of funding, manpower, and time. 4624
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Many organizations are looking outside their company for help in following developments in PAT. The importance of symposiumbased forums like the International Foundation for Process Analytical Chemistry (IFPAC) sponsored by InfoScience (3) for presenting and observing technical developments in PAT is evident based on increased attendance at its recent meetings. In addition, a growing number of meeting based companies (including IBC, CHI, AAPS, IQPC, etc.) are offering workshops and technical presentations in the fields of PAT and QbD (quality by design) on a global basis. Another approach that continues to show value is the concept of leveraging activity via a consortium. Here members of a consortium are able to leverage their resources to fund research projects to develop selected areas of new PAT tools. The most successful consortium of this type in the field of PAT is the Center for Process Analytical Chemistry (CPAC) at the University of Washington in Seattle, Washington. CPAC has been operating now for 25 years and is best characterized as providing value to sponsor organizations from across many industries and government groups. This value is measured by the peer communication forum that has been established, the number of graduates trained in PAT, and the new technologies developed from the research projects. An academic consortium of industrial organizations leverages scarce resources and serves as a benchmarking tool that has proved to be a cost-effective approach to accomplish an understanding of how PAT can be used to achieve QbD leading to product and process optimization. Leveraging also is seen as industry is exposed to additional members of a research team, where funding is provided to only a portion of that research effort. In other words, the center may fund one student in a large group of students and the results of all of the students are usually exposed via posters and presentations at member meetings. It is an interesting dilemma that in the spending reductions by organizations that the value of leveraging with external consortia is not better understood. As the internal resources of an organization are stretched, there seems to be little appreciation by management for the value of leveraging. While it is understandable that it is difficult to maintain external connections when internal resources are being cut, the resulting impact has dramatic implications for long-term technical growth. As a result of the loss of support, there are a growing number of examples where valued academic consortia have disappeared due to a lack of funding from corporations as well as a lack of internal academic support. The result of this dilemma is that to be successful consortia need to be very dynamic in their activities. This requires that their programs continually evolve and adapt to the changing economic environment as well as the evolving technical landscape. To be successful consortia need to constantly be testing the waters to understand which industry segments are growing and what are the technical trends that can support that growth. Presently there is a global interest by all industries in product and process optimization but being verbalized most publically by the pharmaceutical, biotechnology, and food industries. This was seen at a recent workshop on Product and Process Optimization in Siena, Italy, sponsored by IFPAC, CPAC, and the University of Siena (4). The global issues that are affecting governments, industry, and the general public include quality, cost, environment,
energy, safety, and security of products and the processes that produce them. The Siena workshop addressed the status of these topics via plenary lectures and panel discussions. What followed was a series of presentations on the key topics that are addressing and improving the approach to these global issues. The presentations included developments and case studies in (1) quality by design, QbD; (2) process analytical technology, PAT; (3) food quality and safety; (4) bio-processing; (5) green chemistry; (6) nanotechnology; (7) microinstrumentation; and (8) process control and data handling. Since the mid-1990s, CPAC has held a Summer Institute that has focused around the evolving theme of the value of miniaturization of analytical systems as it was believed that this was a way to enhance capabilities, lower cost, and increase analysis speed. This theme was adopted and modified to encompass the emerging field of microsystems (microreactors, microunit operations, etc.) which the participants felt would provide the modularity and flexibility needed to improve future laboratory and process control operations, and that analytical tools needed to be applied to these operations. This proved to be a valuable combination as new developments in microhardware devices had not addressed how these various microunit operations would be monitored and controlled. The combination of microanalytical with microscale production has created a demand for miniaturized sampling, measurement devices, and rapid data handling. Analytical tools that are meshed with laboratory based high throughput experimentation platforms as well as with production based microunit operations provide important new insights into these operations. The CPAC Summer Institute has been an effective venue for gathering engineers, measurement scientists, microinstrumentation vendors, and data handling specialists for presentations and discussions on how to merge microinstrumentation developments with measurement science and engineering needs. The CPAC Summer Institute has proven to be a valuable forum for discussion of evolving industry concerns and the investigation of new technology concepts (4) that can address those concerns. As might be expected, the multidisciplinary and multi-industry forum is able to bring new understandings to form the basis of potential solutions to these complex problems. In addition, the informal atmosphere enables interactions which lead to the formation of various project approaches to problem solving. In recent years, the continuously evolving CPAC Summer Institute theme of microinstrumentation for high throughput experimentation and process intensification has included an emphasis on applications and benefits to bioprocessing. In fact the theme for the Summer Institute of 2009 will be bio-process intensification. Process intensification is based on an understanding of the basic fundamentals of the process and it has gained importance as a way to achieve desired reductions in resource use and waste generation while enhancing productivity and quality of the desired product (5). This topic was expanded upon at the Summer Institute of 2008 relative to the challenges arising with the diversification of the world’s energy sources (6). Miniaturization has proven to be a way to enhance and improve the activities of high throughput experimentation and process intensification. Two significant results of recent CPAC Summer Institutes were in the preparation and publication of a book and the creation of a European based CPAC Satellite workshop. The
meeting agenda is located at the URL found in ref 7. The book on Micro-Instrumentation for High Throughput Experimentation and Process Intensification: A Tool for PAT is a reference book with a multi-industry and multidisciplinary compilation of authors and subjects, similar to the approach used at the Summer Institutes. The specifics of this text are covered in the Books section of this review. The first CPAC Satellite workshop was successfully held in Rome, Italy, in March 2006. The topic selected was microreactors and microanalytical and key international researchers participated. As a result, the workshop has been held each March in Rome and a broader audience has been attracted by incorporating the additional emphasis on biological processes (8). In the late 1990s, industries approached CPAC with a request to serve as a forum for ideas on ways to improve and hopefully standardize process sampling systems. As a result CPAC has served as a focal point for the development of the New Sampling and Sensor Initiative (NeSSI) that is now an ANSI/ISA standard 76.00.02 (9) which defines the footprint of a process sampling system and standardizes the flow geometry of components and interconnects which make up the sampling platform. The use of NeSSI as a sampling system for traditional process analyzers and in process development activities has been a success, as the number of commercial NeSSI units in production use has increased. The platform has been referred to as Generation I of NeSSI. Generation II has been the implementation of data and power systems for the operation of platform components (valves, filters, regulators, etc.) and for diagnostics of those components (10, 11). In addition to being used as an improvement to legacy production sampling systems, NeSSI has now proven to be a template for deploying new microanalytical devices, something that has been called Generation III of NeSSI. A NeSSI platform containing analytical instrumentation can also be used in a number of laboratory based applications. As analytical technologies are developed and/or adapted to be NeSSI compatible, the number of potential applications for a flexible analytical laboratory on a portable NeSSI platform will increase. It is expected that Generation IV will involve applications of NeSSI within production processes, laboratories, and at remote on-site locations as the use of wireless communication is adopted. The success of NeSSI is also demonstrated in it being featured at international expositions by the vendors of the platform and by vendors of the components that are compatible with the platform. Venues for this include CPAC member meetings, the Pittsburgh Conference, IFPAC, and IMTeC (International Micro-Technology Conference). NeSSI has also become a welcome addition as a topic in the CPAC Satellite Workshops in Rome. With the U.S. FDA recent emphasis on the value of product quality, cost, and productivity, the use of process analytical technology (12) has emerged as a way to accomplish quality by design (QbD). The FDA has also worked with the International Committee on Harmonization (ICH) activities to outline an approach for achieving what the small molecule industry has achieved (13). In fact, this outline is an excellent template for all industries to follow in their process development and optimization activities. Analytical Chemistry, Vol. 81, No. 12, June 15, 2009
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An example of how to envision a QbD approach (as incorporated in the International Harmonization Document Q8R) is that an organization should incorporate the following steps in their operations: (1) target the product profile, (2) determine critical quality attributes (CQAs), (3) link raw material attributes and process parameters to CQAs and perform risk assessment, (4) develop a design space, (5) design and implement a control strategy, and (6) manage product lifecycle, including continual improvement. Most of these steps to achieve QbD require the application of PAT tools. In many organizations, groups to evaluate and implement PAT tools as well as groups to study QbD approaches have been established. As a result of this emphasis in the pharmaceutical industry and emerging in the biotechnology industries, the number and type of monitoring tools being commercialized by instrument vendors has been growing and improving. These improvements have occurred in the operation of the measurement systems as well as in the data interpretation of the resulting measurements. The evolution of the importance of the production of biological materials (large, complex molecules in aqueous matrixes) is indeed an area that has a growing appreciation for PAT. Improvements in bioprocessing are of interest to at least three distinct industries. These include pharmaceutical biotechnology, bioenergy, and biobased chemical processes to achieve sustainability goals. In addition, there are related industries such as food, agriculture, and forest products that could be included in those that will benefit from improvements in bioprocessing technology and operations. Bioprocessing normally involves three basic manufacturing steps. These are bioreactors, separations, and product formulation. Bioenergy has received a strong emphasis recently due to rising crude oil prices. The use of biomaterials as a source for hydrocarbons has presented many new challenges to the process engineer, as, for example, the renewed emphasis on separation science to deal with the relatively low concentrations of materials from bioreactors and their cleanup for further processing. An additional focus is on the high energy cost of removing bulk water from products from bioreactors such as ethanol. These are areas where technology improvements are needed. These separation unit operations need to have analytical measurements for monitoring purposes in order to be controlled or optimized. Large molecule production can learn from successes in small molecule manufacturing where “design space” was calculated based on designed variable experimentation. The monitoring tools were then used to gather effective data for the construction of process models. The value of the models built from this monitoring data was seen in establishing process control systems. Monitoring was also the key to continuous improvement activities. The challenges for manufacturing of large (biological) molecules include diverse reaction media including multiphases, sterilization concerns, equipment cleaning, and the potentially large size of some unit operations. These are also key issues for the use of analyzers to characterize process development and ultimately production of these biomolecules since they can make sampling of these unit operations very complicated. Associated with achieving process understanding via use of PAT is the imminent awareness that the quality of raw materials, 4626
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excipients, and nutrients is critical to effectively control the process of interest. This is a very difficult and growing issue due to the complexity of many of these materials, the emerging global purchasing strategies, and need to understand how subtle changes in their composition can impact further processing and final performance. Handling the data from the PAT analyzers continues to be of great interest and the efforts of data mining and data fusion are improving the ability to perform pattern recognition and predictive studies for model and process control improvements. Part of the problem is the large volume of data that can be generated to analyze some of these complex systems. An additional key facet of this problem is that over time the analysis procedure will drift which can add additional complications to understanding and using the data. RESOURCES Consortiums. At this time there are three consortiums involving university, government laboratories, and industrial partners for the purpose of advancing research in process analysis and control technologies that include The Center for Process Analytical Chemistry (CPAC) located at the University of Washington, Seattle, Washington 98195-1700 and The Control Theory and Applications Centre (CTAC), which is based within the School of Mathematical and Information Sciences, Coventry University, Priory Street, Coventry, United Kingdom CV1 5FB. The current URLs for these consortiums are found in the Web Sites section of this review. The Measurement & Control Engineering Center (MCEC) resident at the University of Tennessee, Knoxville, TN, used to be a cooperative venture among The University of Tennessee (UT) College of Engineering, Oak Ridge National Laboratory (ORNL), the National Science Foundation (NSF), and Oklahoma State University College of Engineering, Architecture, and Technology (OSU), with numerous industrial partners (14). Since the previous PAC review, MCEC was disbanded and the Center has been closed. CPAC was established in 1984 to provide a forum for research where costs are shared among sponsors (15). CPAC accomplishes this mission through the sharing of research funding between the University of Washington, corporate research groups, national laboratories, and other government agencies. Involvement in CPAC is intended to help each sponsoring organization develop process control and manufacturing technology. Process monitoring and control is useful for producing better performing products, more efficiently, and with greater safety. Consortiums like CPAC enable process research with reduced cost to sponsors. The reduced cost comes through the sharing of research funding between the member organizations. Core CPAC research areas include chemometrics and process control algorithms, sensors, spectroscopy/imaging, chromatography, flow injection analysis and automated wet chemical methods, and process control devices. The Control Theory and Applications Center (CTAC) is part of the School of Mathematical and Information Sciences at Coventry University (16). CTAC has been designated as a center for process related research since 1992. CTAC’s interdisciplinary research group includes diverse University staff expertise. CTAC has solved real problems across diverse industrial sectors.
Industrial funding supports the majority of CTAC work. CTAC is comprised of a number of research groups performing research in control theory and applications. The research programs and consultancy activities include adaptive control and fault detection, biomedical engineering systems, industrial computing, industrial control applications, computational intelligence and optimization, and robust control system theory and design. The two consortiums described above provide state-of-the-art research covering process control and analytical sensor technologies. CPAC and CTAC provide sponsor organizations the best available research in process control and analysis technologies. A third consortium is called CPACT with its sponsored workshop mentioned in ref 48. CPACT is a multidisciplinary center formed in July 1997 through the Foresight Challenge initiative. This Center brings together chemical and process engineers, analytical chemists, control systems engineers, chemometric experts, signal processing engineers, and statisticians, from academia and industry, to research solutions to generic problems in process monitoring and control. The research is focused on industrial and commercial problems and is applied directly to challenges associated with process manufacturing to produce economic benefit and optimization. Conferences. The main scientific conference covering this topic is the International Forum on Process Analytical Chemistry (IFPAC). This annual conference covers multiple aspects of process analytical technology (17). The conference is generally located in attractive venues and gathers many of the key researchers from process research organizations throughout the world. Further information on IFPAC can be found in the Web Sites section of this review. Web Sites. Web sites provide updated information related to technologies commonly applied for process analytical chemistry; however, the Web sites listed here have very specific process analytical relevance. The URLs listed in this section are not intended to be comprehensive but precisely targeted: Journal of Process Analytical Chemistry (JPAC) (18), http://www.infoscience. com/JPAC/; International Forum on Process Analytical Chemistry (IFPAC) (19), http://www.ifpac.com/; Center for Process Analytical Chemistry (CPAC) (20), http://www.cpac.washington.edu/; The Control Theory and Applications Center (CTAC) (21), http:// www.coventry.ac.uk/researchnet/d/502; Chemometrics Web site link site (22), http://www.chemometrics.se/; U.S. Food and Drug Administration Process Analytical Technology initiative (FDA PAT) (23), http://www.fda.gov/cder/OPS/journalClub.htm. Books. There were many new books specifically relevant to the subject matter of process analytical chemistry published during this review period. The authors identified many applicable texts. Each book is described below, including authors or editors, number of pages, publisher and publication date, ISBN number, and a basic description of the book as relevant to process analytical chemistry. Monitoring and Visualizing Membrane-Based Processes by Carme Gu¨ell, Montserrat Ferrando, and Francisco Lo´pez (Editors), 387 pages, Wiley-VCH; new edition (March 23, 2009), ISBN10: 3527320067. This is a critical review of the main monitoring techniques when applied to membrane processes, demonstrating which technique is most applicable for each type of process. Case studies are provided for monitoring of selected membrane-based
processes. After an introductory section, the book goes on to look at optical and electronic microscopic techniques, followed by electrical, laser, and acoustic techniques, and finishes off with process-oriented monitoring techniques. This book is for researchers and professionals working in the membrane-based process industry (24). Micro Instrumentation for High Throughput Experimentation and Process Intensification: A Tool for PAT by Mel Koch, K. M. VandenBussche, and Ray W. Chrisman, (Editors), 520 pages, Wiley, John & Sons, Incorporated, April 2007, ISBN-13: 9783527314256. This book provides industrial and academic aspects of microinstrumentation, combined with high throughput experimentation and process intensification. This work represents the first comprehensive treatment covering these valuable tools for optimization of manufacturing and production using microinstrument based process analytical technology. Mass and heat transfer measurements can be implemented with microscale equipment, a very active area of instrumentation development rapidly gaining in importance. In process environments, the necessity of producing less waste and more product yield from less starting materials is essential. The impact of safety and environmental issues has led to a novel concept of combining microinstrumentation with process intensification technologies to rapidly gather detailed online process information from high-throughput microreaction equipment. This approach provides a platform for improved understanding of the chemistry and design models required for optimizing production while safely scaling the process more swiftly and at lower costs (25). Formulation and Analytical Development for Low-Dose Oral Drug Products by Jack Zheng (Editor), 461 pages, Wiley; 1st edition (February 9, 2009). ISBN-10: 0470056096. There are unique challenges in the formulation, manufacture, analytical chemistry, and regulatory requirements of low-dose drugs. This book provides an overview of this specialized field and combines formulation, analytical, and regulatory aspects of low-dose development into a single reference book. It describes analytical methodologies like dissolution testing, solid state NMR, Raman microscopy, and LC-MS and presents manufacturing techniques such as granulation, compaction, and compression. Complete with case studies and a discussion of regulatory requirements, this is a core reference for pharmaceutical scientists and regulators involved with pharmaceutical processing (26). Practical Process Control: Tuning and Troubleshooting by Cecil Smith, 431 pages, Wiley-Interscience (January 27, 2009), ISBN10: 0470381930. The focus of this book is troubleshooting, not tuning. The book is intended to provide insight into analyzing and troubleshooting process control systems in process manufacturing plants. The scope of the text stresses practical solutions not requiring complex mathematics. The book focuses on the relationship of process control to steady-state process characteristics rather than to dynamic process characteristics. It demystifies PID control equations by explaining them in the time domain; and it assists in the analysis of process and instrument (P and I) diagrams and demonstrates why they are critical to troubleshooting (27). Magnetic Resonance Microscopy: Spatially Resolved NMR Techniques and Applications by S. L. Codd and J. D. Seymour (Editors), 566 pages, Wiley-VCH, February 2009, ISBN-13: 9783527320080. Analytical Chemistry, Vol. 81, No. 12, June 15, 2009
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This reference handbook covers materials science applications as well as microfluidic, biomedical, and dental applications and the monitoring of physicochemical processes using NMR. It includes the latest in hardware, methodology, and applications of spatially resolved magnetic resonance, such as portable imaging and single-sided NMR spectroscopy. Analogous to hospital use of magnetic resonance imaging (MRI) technology for examination of subjects down to millimeter resolution, process and material scientists also examine materials nondestructively and noninvasively on such microscopic scales. Spatial resolution down to the micrometer range has been achieved, and great efforts are being made to develop magnetic resonance technology for additional applications. Characterization of the structure and transport function of materials is important in applications ranging all the way from biomedicine and food science to geophysics and alternative energy (28). Optical Monitoring of Fresh and Processed Agricultural Crops (Contemporary Food Engineering) by Manuela Zude (Editor), 576 pages, CRC Press (October 29, 2008), ISBN-10: 1420054023. This text takes a task-oriented approach to food processing providing essential applications for a better understanding of noninvasive sensory tools used for raw, processed, and stored agricultural crops and the processing of these products. This volume presents interdisciplinary optical method technologies useful for in situ analyses, including vision systems, visible spectroscopy, nearinfrared spectroscopy, hyperspectral camera systems, scattering methods, time and spatial-resolved measurement approaches, fluorescence spectroscopy, and what the authors’ term sensorfusion (29). Food Process Engineering and Technology (Food Science and Technology) by Zeki Berk, 640 pages, Academic Press (September 22, 2008), ISBN-10: 0123736609. With the combination of scientific depth with practical usefulness, this book serves as a tool for graduate students as well as practicing food engineers, technologists, and researchers looking for the latest information on transformation, preservation, process control, and plant hygiene (30). High-Throughput Analysis in the Pharmaceutical Industry (Critical Reviews in Combinatorial Chemistry) by Perry G. Wang (Editor), 432 pages, CRC Press (August 20, 2008). Highthroughput analysis plays a critical role in the pharmaceutical industry. The ever-shortening timelines and high costs of drug discovery and development have brought about the need for highthroughput approaches to methods that are currently used in the industry. This book systematically describes high-throughput analysis for the pharmaceutical industry, including advanced instrumentation and automated sample preparation. The text discusses various techniques, including HPLC, MALDI-MS, and LC-MS/MS methods, with an emphasis on the later stage of drug development, including their use in pharmacokinetic studies (31). Hyphenated Techniques in Grape and Wine Chemistry by Riccardo Flamini (Editor), 362 pages, Wiley (June 3, 2008), ISBN10: 0470061871. This book presents the modern applications of hyphenated techniques in the analysis and study of the chemistry of grape, wine, and grape-derivative products. Different applications and analytical techniques used in the laboratory are described, such as liquid- and gas-phase chromatography, mass spectrometry, and capillary electrophoresis. The book also covers 4628
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the principal applications of modern sample preparation methods, such as solid-phase-extraction and solid-phase-microextraction during the processes involved in grape and wine chemistry (32). The Management of Chemical Process Development in the Pharmaceutical Industry (Hardcover) by Derek Walker, 416 pages, Wiley-AIChE; (March 28, 2008), ISBN-10: 0470171561. This book broadly discusses management principles involved in chemical process development and a basic description of each discipline involved. This work illustrates practical considerations through many examples of the successful direction and integration of the activities of chemists, analysts, chemical engineers, and biologists, as well as safety, regulatory, and environmental professionals in productive process development and management teams (33). Pharmaceutical Manufacturing Handbook: Production and Processes (Pharmaceutical Development Series) by Shayne Cox Gad (Editor), 1370 pages, Wiley-Interscience; (March 21, 2008), ISBN10: 0470259582. This voluminous handbook represents significant expertise in process analysis disciplines involved in pharmaceutical manufacturing. The work provides detailed information on design, implementation, operations, and troubleshooting for pharmaceutical manufacturing systems. The book is most applicable to pharmaceutical and biotechnology processes (34). Analytical Instrumentation: A Guide to Laboratory, Portable and Miniaturized Instruments by Gillian McMahon, 318 pages, WileyInterscience; (January 14, 2008), ISBN-10: 0470027959. This book describes the principles of analytical instrumentation for chemists and biologists presenting miniaturization of sensors and laboratory-on-a-chip devices. For analytical instrumentation, techniques covered include spectroscopy, chromatography, electrochemistry, imaging, and thermoanalysis methods. There are practical oriented discussions. The book includes applications in healthcare, in environmental applications, and for the pharmaceutical industry. In addition there are sections providing a complete overview of the analytical methods used within the chemical industry (35). Nondestructive Testing of Food Quality (Institute of Food Technologists Series) by Joseph Irudayaraj and Christoph Reh (Editors), 384 pages, Wiley-Blackwell (January 2, 2008), ISBN10: 0813828856. The book focuses on the advances in the food industry and how to optimize the use of analytical instrumentation. The text recommends a strategy which includes product knowledge, process understanding, instrumentation, principles of sensing, process control, and analytical methodology used for successful food process development. Sensor technologies important in food and pharmaceutical industries are described. Analytical methods include ultrasound, near-infrared spectroscopy, midinfrared spectroscopy, Raman spectroscopy, hyperspectral imaging, magnetic resonance imaging, electronic nose technology, z-nose sensors, biosensors, microwave absorption, and the use of nanoparticles and colloids as sensors (36). Process Chemistry in the Pharmaceutical Industry, Vol. 2: Challenges in an Ever Changing Climate by Kumar Gadamasetti and Tamim Braish (Editors), 520 pages, CRC Press; (December 10, 2007), ISBN-10: 0849390516. This volume explores the most up-to-date process research and development methods applied to synthesis, clinical trials, and production of commercial pharmaceutical drug candidates. The book describes synthetic drug manufacturing processes, process safety, and experimental design. A list of covered subjects includes synthesis, instrumentation,
automation, quality control, cost issues, regulatory concerns, outsourcing, green practices, and future trends. The book often uses the case study method to convey information (37). Handbook of Process Chromatography, 2nd edition, Development, Manufacturing, Validation, and Economics (Kindle Edition) by Lars Hagel, Gunter Jagschies, and Gail K. Sofer, 384 pages, Academic Press; (December 5, 2007), ASIN: B001561OEO. This book is an update to the 1997 edition. New emphasis has been placed on the biotechnology and biologics industries related to downstream processing using chromatography and related analytical techniques. The volume describes recovery and purification unit operations as well (38). Additives and Crystallization Processes: From Fundamentals to Applications by Keshra Sangwal, 468 pages, Wiley (December 4, 2007), ISBN-10: 0470061537. Crystal growth is essential for microelectronics, communication technologies, lasers, and energy related materials. The book provides a venue for understanding the interactions between additives and the crystallization phases in different processes. This book presents the mechanisms of additive interactions during nucleation, growth, and aggregation of crystals during the crystallization formation process. Crystallization processes apply to pharmaceuticals, foods, and biofuel production (39). Industrial Process Sensors by David M. Scott, 256 pages, CRC; (November 2, 2007), ISBN-10: 1420044168. This book describes advanced sensor technology used in process control to improve efficiency and product quality. Analysis techniques described include online measurements such as film thickness, particle size, solids concentrations, and contamination detection. The volume reviews the state-of-the-art of the physical principles, design, and implementation of a wide variety of in-process sensors used to control manufacturing operations. The book contains a basic review of the techniques and theory of sensing sound, light, electricity, and radiation. Process sensors to measure temperature, pressure, level, and flow are covered. The book also includes discussions on particle size measurement in slurries and emulsions, tomography and process imaging of manufacturing operations, online measurement of film thickness, identification of polymer type for recycling, and characterization of reinforced polymers and composites (40). Quality Assurance in Analytical Chemistry (Analytical Techniques in the Sciences) by Elizabeth Prichard, Victoria Barwick, 316 pages, Wiley-Interscience; (October 22, 2007), ISBN-10: 047001203X. This book introduces the concept of quality assurance by describing many critical aspects of chemical analysis, from sampling and method selection, to choice of equipment, to the reporting of measurements. Included within the text are details for the implementation and use of quality systems (41). Chemometrics in Spectroscopy by Howard Mark and Jerry Workman, 800 pages, Academic Press (July 24, 2007), ISBN-10: 012374024X. This is a single volume treatment of chemometricbased tutorials for analytical chemists and biotechnologists. This text provides a broad range of mathematics covering the fundamentals of multivariate and experimental data analysis. The work includes many mathematical concepts traditionally useful for process analysis, such as matrix algebra, analytic geometry, experimental design, calibration regression, linearity, design of collaborative laboratory studies, comparing analytical methods,
noise analysis, use of derivatives, analytical accuracy, analysis of variance, and much more are all part of this chemometrics compendium. It is developed in the form of a tutorial offering a basic hands-on approach to chemometric and statistical analysis for analytical scientists, experimentalists, and spectroscopists (42). Process Control: The Passive Systems Approach (Advances in Industrial Control) by Jie Bao and Peter L. Lee, 253 pages, Springer; (July 12, 2007), ISBN-10: 1846288924. This book covers an emerging area in process control: control system analysis and design based on the concept of passive systems. Passive systems are a class of processes that dissipate certain types of physical or virtual energy, defined by Lyapunov-like functions. In this book, passivity-based developments in the areas of robust process control, decentralized control, fault tolerant control, process controllability analysis, and nonlinear process control are addressed. The text emphasizes case studies in all the main chapters. MATLAB routines for selected examples and a library of functions that implement the system analysis and control design methods can be downloaded from the publisher (43). UV-Visible Spectrophotometry of Water and Wastewater, Vol. 27 (Techniques and Instrumentation in Analytical Chemistry) by Olivier Thomas and Christopher Burgess (Editors), 372 pages, Elsevier Science; (April 27, 2007), ISBN-10: 0444530924. This book is exclusively on the subject of the use of UV spectrophotometry for water and wastewater quality monitoring. This technique provides a rapid or process implementable method for nitrate and total organic carbon (TOC). UV spectrophotometry simultaneously provides qualitative information on the global composition of water. The book includes the first electronic library of UV-spectra providing data readily available for researchers and users, a theoretical basis for further research in the field of spectra exploitation, and helpful practical examples and applications (44). Chemometrics: Statistics and Computer Application in Analytical Chemistry by Matthias Otto, 343 pages, Wiley-VCH; 2nd edition (April 20, 2007), ISBN-10: 3527314180. This new edition contains more worked examples than the previous edition with the inclusion of chemometric methods. Chemometric methods included are support vector machines, wavelet transformations and multiway analysis, relevant statistics, fuzzy theory, databases, and quality assurance methods (45). New Frontiers in Ultrasensitive Bioanalysis: Advanced Analytical Chemistry Applications in Nanobiotechnology, Single Molecule Detection, and Single Cell Analysis, Analytical Chemistry and Its Applications by Xiao-Hong and Nancy Xu (Editors), 308 pages, Wiley-Interscience; (April 13, 2007), ISBN-10: 0471746606. This book describes new platforms used for ultrasensitive analysis of biomolecules and single living cells using multiplexing, single nanoparticle sensing, nanofluidics, and single-molecule detection. This book provides an overview of the current state of ultrasensitive bioanalysis. Included are single molecule detection (SMD), single living cell analysis, multifunctional nanoparticle probes, miniaturization, multiplexing, and quantitative and qualitative analysis of metal ions and small molecules. Techniques are included such as single molecule microscope and spectroscopy, single nanoparticle optics, single nanoparticle sensors, micro- and nanofluidics, microarray detection, ultramicroelectrodes, electrochemiluminescence, and mass spectrometry (46). Analytical Chemistry, Vol. 81, No. 12, June 15, 2009
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The reviewers also note there are many books on the use of process related software. These include MathCad, VisSim, LabVIEW, MATLAB, and others. There are new versions and supplements released on a regular basis. A basic search of the Web using these software names as the primary search term uncovers many useful texts. These software packages have become fairly standard among academic and industrial process algorithm test developers, and the code for basic algorithms is often shared among users or user groups. Workshops. Workshops emphasizing process analytical chemistry in modern chemical process industries are held on a regular basis. One such workshop is held periodically and sponsored by various industrial research groups and the Center for Process Analytical Chemistry at the University of Washington, Seattle, and is called CPAC Summer Institute, University of Washington, Seattle, Washington. The International Symposium on Advanced Control of Chemical Processes (ADCHEM) is held every 3 years. The next ADCHEM will be held in 2009 on Koc¸ University’s campus which is located at the meeting point of the Bosphorous with the Black Sea. It is close to the city of Istanbul but at the same time far removed from the city’s distractions. It is cosponsored by the Chemical Process Control, Nonlinear Control Systems, and SAFEPROCESS Technical Committees of the International Federation of Automatic Control (IFAC). Following the tradition of the previous ADCHEM symposia held in Toulouse (1991), Kyoto (1994), Banff (1997), Pisa (2000), Hong Kong (2003), and Gramado (2006), ADCHEM 2009 will bring together researchers and practitioners to discuss the recent developments in control of chemical, biochemical and closely related process systems. Both theory and applications will be covered. Meeting topics include process modeling and identification, advanced process control, strategies, process and control monitoring, plantwide control, process control applications, and emerging methods and technologies (47). A workshop called APACT 2009 (Advances in Process Analytics and Control Technology) will be held in Glasgow for 2009. The Conference proposes a discussion of topics around the theme “Process Analysis and Control for Profit.” The URL for this workshop is found at http://www.cpact.com/apact/apact.html. The conference is scheduled for May 5-7, 2009. This workshop is sponsored by The Center for Process Analytics and Control Technology (CPACT) (48). National Laboratories. The national laboratories often participate in research for development of advanced sensor technologies, many of which are applicable to process analytical challenges. The emphasis on high-performance, rugged, intelligent and smaller sensors fits well with the mission of process analysis to measure chemical and physical property information of chemical processes in real-time and in situ when possible. New monitoring systems are often developed by Pacific Northwest National Laboratory (PNNL). Pacific Northwest National Laboratory provides scientific and technology development tailored to meet client/project needs and include scientific investigations and analyses, feasibility studies, measurement and data analysis method development, validation and application, laboratory testing, prototype sensor and equipment development and evaluation, and development and deployment of field-hardened 4630
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equipment and methods. PNNL has developed a broad range of sensors to meet requirements for biological sensors, chemical sensors, physical property sensors, and nuclear radiation sensors. Sandia National Laboratories has been focusing in recent years on microanalytical systems. These include hand-held, miniature, or portable instruments built around microfabricated components, such as microelectromechanical systems (MEMS) devices. Recent developments at Sandia include: (1) a new microcalibrator chip, consisting of a thermally labile solid matrix on an array of suspended-membrane microhot plates that when actuated delivers controlled quantities of chemical vapors, (2) micrometer-scale cylindrical ion traps, fabricated using a molded tungsten process, which form the critical elements for a micromass analyzer systems, and (3) monolithically integrated microchemical analysis systems fabricated in silicon. These tiny analytical systems enable integration of chemical preconcentrators, gas chromatographic columns, detector arrays, and MEMS valves. The Chemical Science and Technology Laboratory (CSTL) of the National Institute of Standards and Technology (NIST) is involved in the development and improvement of sensor technologies for a wide variety of analytical applications, including those used for process analysis. Instrument manufacturers depend on NIST/CSTL for data, and physical and chemical standards for instrument calibration, and providing traceability to national standards to the end users of their products and instruments. CSTL provides a breadth of resources that support the pharmaceutical industry including reference data as well as artifact standards, such as optical filters and fluorescence standards used for instrument calibration. CSTL measurements and standards facilitate the drug discovery process, help optimize production of new pharmaceuticals, and ensure quality control in manufacturing processes. In addition, CSTL’s fundamental work in enzyme characterization promotes the transition to biomanufacturing leading to more environmentally sustainable manufacturing. MICROANALYTICAL SYSTEMS Microelectromechanical Systems. MEMS based sensors are analytical instruments in miniaturized packaging. Microscale and nanoscale sensors are disruptive technologies allowing miniaturization of complex sensor platforms. For multiple unit deployment, they have reduced cost of assembly and reduced cost of goods and can be manufactured more reproducibly than current macrotechnologies. They are more adaptable to high throughput or microreactor applications, automation, in situ placement, medical applications, and multitechnologies in the same instrument package (e.g., LC, GC, UV, NIR, IR, Raman, MS). In addition they are green friendly (e.g., utilize fewer natural resources and are easier to dispose of due to small size). They are adaptable to the future of microreactors and small sensors in everyday life. They have the potential for higher performance overall for separation sciences and optical sciences. This is due to the decreased sample requirements and the unique and special flow dynamics of nanochannels or microchannels. For optical devices, these systems can accommodate increased complexity in optical design with greater precision (Angstrom level alignment). They require smaller optical paths, less mass means reduced temperature, humidity, and vibration sensitivity for optical systems, and they can utilize simpler and higher performing electronics mainly due to the reduced requirement for power consumption.
High-speed, highly sensitive, miniature photospectroscopy techniques suited for a microfluidic platform are reported for rapid, cost-effective, and efficient assays. A tunable diffraction grating for spectroscopic measurements requiring minimal optics and signal processing was designed and tested. The device includes a flexible polymer microbridge with a nanoimprinted grating pattern on the uppermost surface. Microelectromechanical system silicon actuators mechanically strain the microbridge to variably tune the grating period. Nanophotonic technology incorporating the tunable grating may guide future advancements of wavelengthdiscriminating detection for the identification and quantification of chemical and biological species in process environments or other applications (49). The development of explosive detection with MEMS technology was reviewed. Various detecting methods were classified in microcalorimetric spectroscopy, optical displacement measuring, resonance frequency shift measuring, piezoresistive strain monitoring, heat absorption or release monitoring, and FA-IMS. Advantages and disadvantages of each method were respectively discussed (50). Electrically injected MEMS-tunable vertical-cavity surfaceemitting lasers with emission wavelengths below 800 nm were described. Operation in this wavelength range, near the oxygen A-band from 760-780 nm, is attractive for absorption-based optical gas sensing. These fully monolithic devices are based on an oxideaperture AlGaAs epitaxial structure and incorporate a suspended dielectric Bragg mirror for wavelength tuning. By implementation of the electrostatic actuation, the potential for tuning rates up to 1 MHz as well as a wide wavelength tuning range of 30 nm (767-737 nm) were demonstrated (51). Micro Total Analytical Systems (µTAS). The concept micro total analytical systems (µ-TAS), also termed “laboratory-on-achip”, and the latest progresses in the development of microfabricated separation devices and on-chip detection techniques are continuing to advance in development and deployment. Specific applications of microanalytical methods for process, bioanalytical, and pharmaceutical studies involve chemical reaction monitoring and analytical separations of biomolecules on microscale levels. A comprehensive review article entitled, “Micro Total Analysis Systems: Latest Achievements” has been written covering the topic literature up until 2008 (52). A critical requirement for achieving a micro total analytical system for the analysis of cells and their constituent proteins is to integrate the lysis and fractionation steps on-chip. An experimental microfluidic system integrating the lysis of bacterial cells and the extraction of a large intracellular enzyme, β-galactosidase, has been demonstrated. The β-galactosidase is detected and quantified using a fluorogenic enzyme assay and a numerical model. While the focus is on the lysis of typical Gramnegative bacterial cells (E. coli), the techniques described here could, in principle, be applied to a variety of different cell types in an automated process (53). Microanalytical. The term microanalytical systems refers to the trend in making ever more sophisticated and capable sensor and analyzer systems in smaller packages and adding automation and intelligence to these sensors for improved operations. The key drivers for these developments are specialized applications requiring microscale devices, such as microreactors, medical devices, in situ sensing, hazard monitoring, and others.
A digital signal readout protocol for screening disk-based bioassays with standard optical drives of ordinary desktop/ notebook computers is described. Three different types of biochemical recognition reactions (biotin-streptavidin binding, DNA hybridization, and protein-protein interaction) were performed directly on a compact disk in a line array format with the help of microfluidic channel plates. This readout protocol is about 1 order of magnitude more sensitive than fluorescence labeling/ scanning and has the capability of examining multiplex microassays on the same disk. Because no modification to either hardware or software is needed, it promises a platform technology for rapid, low-cost, and high-throughput point-of-care biomedical diagnostics (54). Microfluidics. Microchannel fluid flow research explores the potential of hydrogels for biological assays of high specificity in areas such as biosensing, biological interaction, and diagnosis of disease. The conventional approach to developing such methods, particularly in areas of protein analysis, involves surface immobilization of probes to microchannel walls using surface chemical and/or streptavidin/biotin linkages through multistep or coupled chemical reactions. Hydrogel plugs provide another approach for immobilizing probes in microchannels. Sensors can be easily formed in microchannels within minutes by incorporating antibody probes in the monomer solution. Upon polymerization using a photoinitiator, these probes are immobilized by physical entrapment. Hydrogel sensors capable of specific capture of target antigens demonstrate the potential of this technology for protein based assays. An array of four sensing microdome optodes (potassium, sodium, calcium, and chloride) was incorporated into a centrifugal microfluidics platform to obtain a multiion analysis system. The selectivity of each optode over common interfering ions was established and was used to identify calibrant solutions that can be employed for the simultaneous calibration of all four optodes without significant cross-interference. The microfluidic platform was designed to facilitate both three-point calibration of the optodes and triplicate analysis of a sample within a single run, which increases the accuracy of the determination. The optimized microfluidic system was used to determine simultaneously the concentration of potassium, sodium, calcium, and chloride in aquarium water with less than 6% relative error. The simple process of fabrication of these microdomes and their incorporation into a centrifugal microfluidic platform should facilitate the development of portable ion-sensing analysis systems (55). A microfluidic system is developed in which mass exchanges take place between moving water droplets, formed on-chip, and an external phase (octanol). At this interface, no chemical reaction takes place and the mass exchanges are driven by a contrast in chemical potential between the dispersed and continuous phases. The specific case studied involves microfluidic droplets, occupying the entire width of the microchannel, extract a solute, fluorescein, from the external phase (extraction) and the opposite case, where droplets reject a solute, rhodamine, into the external phase (purification). Four flow configurations are investigated with an analysis of the influence of different parameters on the process: channel dimensions, fluid viscosities, flow rates, drop size, and droplet spacing (56). Analytical Chemistry, Vol. 81, No. 12, June 15, 2009
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Microreactors. Multiple developments have occurred over the review period for microreactor design and implementation into pharmaceutical and chemical syntheses, particularly in plant concepts, fluidic and electronic interfaces and platforms, sensory and analytical devices, and process automation. A multistep enzyme reaction on a chip was used to determine the key kinetic parameters of an enzyme reaction. A fully integrated microfluidic chip was designed and fabricated to have sample metering, mixing, and incubation features. The chip generated a gradient of reagent concentrations in 11 parallel processors. β-galactosidase and its substrate, resorufin-β-D-galactopyranoside, were used as the model system of the enzyme reaction. With a single experiment on the chip, the key parameters for the enzyme kinetics, Km and kcat, were determined and the effect of inhibitor concentrations on the reaction rates was determined (57). A novel solid state optical detection platform, integrated in a plastic biochip, based on colloidal nanocrystal FRET donors was designed and fabricated. The approach exploits a “smart” polymeric layer with both optical and biorecognition properties that allows real-time monitoring of biomolecular interactions and quantitative analyses of real-time PCR. The proposed strategy, demonstrated for DNA detection, may be applicable to a wide range of applications, such as proteomic studies (58). A KOH-catalyzed synthesis of biodiesel was carried out in capillary microreactors with inner diameters of 0.25 or 0.53 mm. Unrefined natural products as rapeseed oil and cottonseed oil were used as raw materials. The influences of the methanol to oil molar ratio, the residence time, the catalyst concentration, the reaction temperature, and the dimension of the capillary on the production of biodiesel were examined. The results indicated that the residence time was greatly reduced by using microchannel reactors, compared to a conventional batch reactor. The reaction temperature was the minimal factor in the yield of methyl ester. Meanwhile, the methyl ester yield first increased with the methanol/oil ratio and then decreased due to emulsion and saponification. The inner diameter of the microchannel reactor had a strong influence on the transesterification reaction. Higher methyl ester yield could be obtained at shorter residence times for the microchannel reactor with the smaller inner diameter (59). Nanotechnology. The effort to fabricate and study smaller components, systems, and devices are activities occupying significant research time and money in the current technology landscape. The term “nano” is not only trendy but also ubiquitous in technology discussions. Everything from “nanobots” or small intelligent devices, to nanodots, to nanoparticles, materials, and systems are discussed. These ever “shrinking” technologies are being studied for potential application into today’s research and development plans. The proliferation of nanoparticles is raising concern from environmentalists and health specialists who are responsible for the health effects on humans, on animals, and to the long-term impact on ecosystems of the global environment. With new and improved technologies as well as new applications for existing technology, the search for new drugs for the prevention and treatment of human diseases continues. The changing nature of technologies and methods used for chemical analysis is directly relevant to the pharmaceutical industry today. Successful application of such technologies opens new opportuni4632
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ties for drug discovery and construction of a new composition of matter. Field effect transistors (FETs) based on random networks (RNs) of single-wall carbon nanotubes (CNTs) have produced several technological advantages. However, the low sensitivity (or no sensitivity) of RN-CNT sensors to nonpolar molecules is a problematic, negative feature that limits their applications in the detection of a wide variety of diseases via breath samples. In this paper, experimental evidence for the detection of both individual nonpolar molecules and patterns of nonpolar molecules, even in the presence of polar molecules in the same environment, are demonstrated. RN-CNT FETs are prepared and functionalized with organic films that exhibit distinctive electrical and physical (or mechanical) characteristics. Exposing the functionalized RN-CNTs to representative nonpolar breath biomarkers and, for comparison, to polar molecules in the gas phase, and monitoring the changes in conductance, work function, and organic film thickness shows sensitivity toward nonpolar molecules. The sensitivity toward nonpolar molecules can be tailored, even in the presence of polar molecules, by controlling the scattering of charge carrier through deliberate functionalization of CNTs. Examples for the technological impact of this work are descriptions of lung cancer and kidney disease detection using specially designed RN-CNT sensor arrays (60). BIOSENSORS Sensor Development. Biosensors are comprised of detection technology utilizing enzymes or other biomolecules to sense information relative to biological systems or to mimic biological sensing processes. There is a great deal of electrochemical work occurring in this area, and the reader is referred to that subject area for additional information on biosensing techniques. Biosensors have successfully been applied to detect multiple pathogens simultaneously at very low levels. Miniaturization of biosensors is required for field or point of care (POC) use. Optical components suitable for integration-such as light-emitting diodes (LEDs) and complementary metal-oxide semiconductor (CMOS) chips are generally still too expensive for disposable components within biosensors. This paper describes the integration of polymer diodes onto a biosensor chip to create a disposable device that includes both the detector and the sensing surface coated with immobilized capture antibody. A chemiluminescence immunoassay was performed on the OPD substrate, and the results were measured using a hand-held reader attached to a laptop computer. The miniaturized biosensor with a disposable slide, which included an organic photodiode, detected Staphylococcal enterotoxin B at concentrations as low as 0.5 ng/mL (61). A single nanoparticle tracking-based detection method for membrane-associated molecules was fabricated using a paucivalent gold nanoparticle, (AuNP)-modified supported lipid bilayer (SLB) platform. The binding activity of membrane-associated molecules (cholera toxin binding to ganglioside GM1 in this case) was determined by calculating the diffusion coefficients of membranetethered AuNPs. This nonbleaching nanoparticle-based method provides >100-fold improvement in sensitivity for the same target without optimization over the fluorophore-based method that also has photobleaching and photoblinking problems. This new detection platform and analysis method could be used for
membrane-associated molecule biosensor and screening assay development (62). Biological Agent Detection. Specialized sensors to detect biological agents hazardous to the environment and to the national security are under development. There is classified work in this area and many of the sensor and detection technologies discussed in the various sections of this review are applicable or are under investigation for detection of biohazardous materials. Magnetic nanoparticles functionalized with anti-Escherichia coli O157:H7 or anti-Salmonella typhimurium antibodies that can specifically bind to their target organisms were used to isolate E. coli O157:H7 and S. typhimurium separately from a cocktail of bacteria and from food matrixes. The pathogens were then detected using label-free IR fingerprinting. The binding and detection protocol was first validated using a benchtop FT-IR spectrometer and then applied to a portable mid-IR spectrometer to enable this approach as a point-of-detection technology. Highly selective detection was achieved in less than 30 min for (E. coli O157:H7 vs S. typhimurium) and strain (E. coli O157:H7 vs E. coli K12) in complex food matrixes (2% fat milk and spinach extract) with a detection limit of 104-105 CFU/mL. The combined approach of functionalized magnetic nanoparticles and IR spectroscopy imparts specificity and could be applied in the field for on-site food-borne pathogen monitoring (63). A rapid method was presented for the identification of viruses using microfluidic chip gel electrophoresis (CGE) of high-copy number proteins to generate unique protein profiles. Viral proteins are solubilized by heating at 95 °C in borate buffer containing detergent (5 min), then labeled with fluorescamine dye (10 s), and analyzed using the µChemLab CGE system (5 min). Analyses of closely related T2 and T4 bacteriophage demonstrate sufficient assay sensitivity and peak resolution to distinguish the two phages. CGE analyses of four additional viruses, MS2 bacteriophage, Epstein-Barr, respiratory syncytial, and vaccinia viruses, demonstrate reproducible and visually distinct protein profiles. To evaluate the suitability of the method for unique identification of viruses, a Bayesian classification approach was used. A subset of 126 replicate electropherograms of the six viruses and phage was used for algorithm training purposes. A successful classification with nontraining (validation) data was 66/69 or 95% with no false positives. The results suggest a rapid and simple way to identify viruses without the need for specialty reagents, such as PCR probes and antibodies (64). CHEMICAL DETECTION Chemical Agent Detection. A variety of spectroscopic and electrochemical sensors are under development for these applications. The electrochemical, chromatographic, mass detection, conductive polymers, specialized sensors, and molecular spectroscopy technologies are most applicable. A new approach for improving the compatibility between contact conductivity detection and microchip electrophoresis was developed. Contact conductivity has traditionally been limited by the interaction of the separation voltage with the detection electrodes because the applied field creates a voltage difference between the electrodes, leading to unwanted electrochemical reactions. To minimize the voltage drop between the conductivity electrodes, a novel bubble cell detection zone was designed. The bubble cell permitted higher separation field strengths (600 V/cm)
and reduced background noise. The impact of the bubble cell on separation efficiency was measured by imaging fluorescein during electrophoresis. A commercial chromatography conductivity detector (Dionex CD20) was used to evaluate the performance of contact conductivity detection with the bubble cell. Mass detection limits (S/N ) 3) were as low as 89 ± 9 amol, providing concentration detection limits as low as 71 ± 7 nM with gated injection. The linear range was measured to be greater than 2 orders of magnitude, from 1.3 to 600 µM for sulfamate. The bubble cell design improves the compatibility and applicability of contact conductivity detection in microchip electrophoresis, and similar designs may have broader application in electrochemical detection (65). SAMPLING AND NEW SAMPLING SYSTEMS NESSI. The emergence and continued development of miniature, modular sample system technology in the chemical processing industry has established a platform to drive the development of improved miniaturized analytical technology; this technology is termed the New Sampling/Sensor Initiative (NeSSI). Miniature, modular sample conditioning substrates, and components have been used for many years in the semiconductor industry and have proven to be an effective and reliable technology for regulating and controlling the corrosive vapor sample streams common to this industry. Basic review articles contain much of the current information on process sampling systems. ELECTROCHEMISTRY OR ELECTROPHORESIS Electrochemistry is growing in importance as specialized sensor arrays are being applied to medical, chemical, environmental, and hazardous detection applications. These sensors are highly specific and low cost and can be made with intelligence integrated into the analysis systems by use of sophisticated algorithms and multichannel array data analysis approaches. Electronic nose and tongue technologies using array-based sensors and data processing schemes are providing increased utility as sensitive detection technologies. Chemical cytometry performed by capillary electrophoresis (CE) has become increasingly valuable as a bioanalytical tool to quantify analytes from single cells during the past decade. Extensive use of CE-based chemical cytometry has been reduced by the relatively low throughput for the analysis of single adherent cells. In order to improve the utility of CE-based analysis, new higher throughput methods are needed. Integration of a coaxial buffer exchange system with CE-based chemical cytometry has demonstrated increased rate of serial analyses of cells. In the reported design, fluid flow through a tube coaxial to the separation capillary was used to supply electrophoretic buffer to the capillary. This sheath or coaxial fluid was turned off between analysis of cells and turned on during cell sampling and electrophoresis. Key parameters of the system such as the relative capillary-sheath positions, buffer flow velocities, and the cell chamber design were optimized. To demonstrate the improved throughput of the system, rat basophilic leukemic cells loaded with Oregon green and fluorescein were serially lysed and loaded into a capillary. Separation of the contents of 20 cells at a rate of 0.5 cells/min was demonstrated (66). Analytical Chemistry, Vol. 81, No. 12, June 15, 2009
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CHROMATOGRAPHY LC-MS/MS. Trends continue in the research and development of multidimensional and hyphenated chromatographic techniques. These methods provide more information from chromatograms for discrimination of complex mixtures of biomolecules or natural products with much more power than traditional first-order chromatography. Computational power is providing additional access in real-time to such methodologies for accurate and rapid analysis of complex chemical and biological mixtures. A visualization approach was developed for the identification of protein isoforms, precursor/mature protein combinations, and fragments from LC-MS/MS analysis of multidimensional fractionation of serum and plasma proteins. A pattern recognition algorithm was used to automatically detect and flag potentially heterogeneous species of proteins in proteomic experiments that involve extensive fractionation and result in a large number of identified serum or plasma proteins in an experiment. Potential applications include identification of differentially expressed isoforms in disease states (67). GC/MS. This technique is used to determine the presence of detailed chemical composition for a variety of chemical compounds and mixtures. One particular area of research interest is the analysis of botanical and herbal chemistry for human consumption of nutraceuticals and dietary supplements. Liquid Chromatography. Imaging time-of-flight secondary ion mass spectrometry (TOF-SIMS) was used as a high-throughput analytical tool for combinatorial chemical research. Other techniques have been combined with LC-MS to produce a new arsenal of powerful hyphenated techniques for a variety of analytical work. Examples are given in this section as LC-MS-NMR and LC-MS-MDF. LC-MS-NMR. An LC-MS-NMR platform combining two innovations in microscale analysis, nanoSplitter LC-MS and microdroplet NMR, was demonstrated for the identification of unknown compounds encountered in metabolomics or natural products discovery. The nanoSplitter provides the high sensitivity of nanoelectrospray MS while allowing 98% of the HPLC effluent from a large-bore LC column to be collected and concentrated for NMR. Microdroplet NMR is a droplet microfluidic NMR loading method providing several fold higher sample efficiency than conventional flow injection methods. Performing NMR offline from LC-UV-MS accommodates the disparity between MS and NMR in their sample mass and time requirements as well as allowing NMR spectra to be requested retrospectively after review of the LC-MS data. Interpretable 1D NMR spectra were obtained from analytes at the 200 ng level, in 1 h/well automated NMR data acquisitions. The system also showed excellent intra- and interdetector reproducibility with retention time RSD values less than 2% and sample recovery on the order of 93%. When applied to a cyanobacterial extract showing antibacterial activity, the platform recognized several previously known metabolites, down to the 1% level, in a single 30 µg injection and prioritized one unknown for further study (68). LC-MS-MDF. A mass defect filter (MDF) approach was applied to the screening and identification of reactive metabolites using high-resolution mass spectrometry. Glutathione (GSH)trapped reactive metabolites of acetaminophen, diclofenac, car4634
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bamazepine, clozapine, p-cresol, 4-ethylphenol, and 3-methylindole in human liver microsomes (HLM) were analyzed by HPLC coupled with Orbitrap or Fourier transform ion cyclotron resonance mass spectrometry. The accurate mass LC-MS data sets were utilized for the elimination of false positive peaks, detection of stable oxidative metabolites with other MDF templates, and determination of metabolite molecular formulas. Compared to a neutral loss scan using a triple quadrupole instrument, the MDF approach demonstrated greater sensitivity and selectivity in screening for GSH-trapped reactive metabolites in HLM and rat bile. The approach also demonstrated far more effective detection of GSH adducts that do not afford the neutral loss of 129 Da as a significant fragmentation pathway. The GSH adduct screening capability of the MDF approach, together with the utility of accurate mass MS/MS information in structural elucidation, makes high-resolution LC-MS and MDF a useful tool for analyzing reactive metabolites (69). SPECTROSCOPY UV-Visible Spectroscopy. New developments in this technique include commercial versions of UV-vis imaging systems, attenuated total reflection (ATR) spectroscopy, FT-UV spectroscopy optimization, and various applications of fiber optic based and high-resolution techniques. Solid state UV-visible spectroscopy was used to characterize a subnanometer pattern of mixed chemical functional groups that were fabricated on the surface of silica. The pattern consisted of thiol and primary amine functionalities. This approach has required the development of a synthetic method for the thermolytic imprinting of thiols based on a xanthate protection scheme, which enables bifunctional imprints containing carbamate and xanthate functionality to be condensed onto a silica surface and thermolytically deprotected in a single step. This imprinting process is demonstrated for the synthesis of bifunctional imprinted sites containing thiol-amine pairs and groups of two thiols and an amine per imprinted site. Additional techniques used to characterize these surfaces included 29Si CP/MAS NMR and 13C CP/ MAS NMR spectroscopies. Independent titration of thiols with Ellman’s reagent and amines with perchloric acid demonstrates that the bulk surface coverage of thiol and amine functionality reflects the expected ratios based on imprint molecule stoichiometry, with yields of accessible bifunctional imprinted sites greater than 80% relative to the amount of imprint used (70). Fluorescence. Fluorescence continues to prove itself as an ultrasensitive and potentially selective analytical technique. Fluorescent probe chemistries and immuno labeled binding fluorescent chemistries have become essential tools in biomedical discovery research. Fluorescence is also applicable for process or flow system analysis. The technique is improving and continuing to be of general interest to analytical scientists and for process measurements. Optimization and improvements of conventional fluorescence spectrometer geometry were reported. The most widely used correction of fluorescence intensities for inner filter effects in conventional (90°) fluorimeters fails at high absorbance values. This work critically examined this failure, which is caused by the difference between the geometrical parameters (GPs) of the excitation and emission beams in the typical commercial instrument design (focused beams) and in the theoretical picture on
which the correction is based (collimated beams). The authors provided two types of experimental measurement of GPs and show that their substitution in the correction equations leads to significant improvements in the linear range of corrected fluorescence. Mathematical optimization was also shown to yield greater improvements and that the optimizations yield GPs consistent with experimental measurements. For solutions exhibiting the primary inner filter effect only, the design improvements extended the range of linearity of corrected fluorescence to aex (absorbance per cm) up to 5.3; for systems with both primary and secondary inner filter effects, we have achieved linearity for aex + aem ) 6.7. In all cases, linear fits have slopes which agree well with the dilute limit. Different series of one- and two-solute solutions were used to demonstrate effectiveness of these correction methods. This work provides a rationale for the unexpected independence of GPs on excitation and emission bandwidths (71). Imaging. A variety of analytical techniques have been adapted to provide chemical response intensity data at different measurement channels while including spatial information. These data hypercubes can be useful for chemical, optical, and physical property measurements as related to physical structures. The use of chemical imaging is a developing area which has potential benefits for chemical systems where spatial distribution is important. Examples include processes in which homogeneity is critical and dynamic processes where spatial distribution of chemical compounds is important. While single images can be used to determine chemical distribution patterns at a given point in time, dynamic processes can be studied using a sequence of images measured at regular time intervals compressed into a movielike format. A technique was reported that utilizes surface plasmon resonance (SPR) dispersion as a mechanism to provide multicolor contrast images of thin molecular films. Illumination of gold surfaces with p-polarized white light in the Kretschmann configuration produces distinct reflected colors due to excitation of surface plasmons and the resulting absorption of specific wavelengths from the light source. These color patterns transform in response to the formation of thin molecular films. This process represents a simple detection method for distinguishing between films of varying thickness in sensor applications. A protein microarray formed by a commercial drop-on-demand chemical ink jet printer was tested. Submonolayer films of bovine serum albumin (BSA) test protein were easily detected by this method. Higher detection sensitivity was achieved at angles where red visible light wavelengths coupled to surface plasmons. However, improved contrast and spatial resolution occurred when the angle of incidence was such that shorter wavelengths coupled to the surface plasmons. Simplified optics combined with the robust microarray printing platform are used to demonstrate the applicability of this technique as a rapid and versatile, highthroughput tool for label-free detection of adsorbed films and macromolecules (72). Spectroscopic imaging has become a widely used tool for analyses of heterogeneous samples. Focal plane array (FPA) detectors are incorporated into spectrometers that acquire a large number of spectra from different sample locations in parallel. This sensing technique facilitates analyses of spatial distributions of
chemical information in an X-Y plane at high time resolution. In many cases, chemical reactions proceed in three spatial dimensions (X-Y-Z) and require the acquisition of spectroscopic information in an X-Y plane plus topographic (Z-dimension) information. However, capturing two-dimensional (2D, i.e., X-Y) images from three-dimensional (3D, i.e., X-Y-Z) samples inherently loses Z-dimension information. An augmented spectroscopic imager is demonstrated that gains both types of data, i.e., spatially resolved spectroscopic information and topography simultaneously. For topography data collection, a regular light pattern is generated and projected onto a sample. Because of its 3D topography, this light pattern is distorted. After extraction of these distortions, the topography can be determined since the height structure is encoded in the light pattern. Because topographic probing must not affect infrared measurements, different wavelength ranges are used. Here spectroscopic information is acquired in the mid-IR while the light pattern probing the topography is generated in the visible. For relation of distortions to physical height structures, the setup needs to be calibrated. For this purpose, calibration objects of known dimensions have been manufactured onto which the light pattern is projected. Determining distortions introduced by objects of known height derives a transform from distortions to topographies. Because of mechanical restrictions, the light pattern can only achieve a certain spatial resolution. In order to enhance the spatial resolution the topography is probed with, the light pattern is scanned in the X- and Y-direction (73). Infrared Spectroscopy. The use of infrared spectroscopy for process analysis and in situ measurements is widely accepted. More exotic uses of this technique are described here in concert with a host of complementary analytical techniques for a powerful analysis toolkit. Diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) and transmittance-FT-IR (T-FT-IR) were used to analyze organic and inorganic components in single samples for field collected archeological samples. Excavations at the 14th century Moorish rampart (Granada, Spain) unearthed a brick oven alongside black ash and bone stratigraphic layers. In situ evidence suggests the oven served to fabricate a wall coating including powdered burnt bones. Original ad hoc analyses improved on conventional methods were used to confirm this hypothesis. These methods enable (i) nondestructive micro-X-ray diffraction (µ-XRD) for fast mineralogical data acquisition (10 s) and moderately high spatial (500 µm) resolution and (ii) identification and imaging of crystalline components in sample cross sections via mineral maps, yielding outstanding visualization of grain distribution and morphology in composite samples based on scanning electron microscopy-energy dispersion X-ray spectrometry (SEM-EDX) elemental maps. In addition to infrared spectroscopy, complementary techniques to fully characterize artifacts were GC/MS, optical microscopy (OM), conventional powder XRD, and 14C dating. Bone-hydroxyapatite was detected in the coating. Mineralogical transformations in the bricks indicate oven temperatures well above 1000 °C, supporting the hypothesis (74). Synchrotron Fourier transform infrared (FT-IR) spectra of fixed single erythrocytes infected with Plasmodium falciparum at different stages of the intraerythrocytic cycle are presented for Analytical Chemistry, Vol. 81, No. 12, June 15, 2009
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the first time. Bands assigned to the hemozoin moiety at 1712, 1664, and 1209 cm-1 are observed in FT-IR difference spectra between uninfected erythrocytes and infected trophozoites. These bands are also found to be important contributors in separating the trophozoite spectra from the uninfected cell spectra in principle components analysis. All stages of the intraerythrocytic lifecycle of the malarial parasite, including the ring and schizont stage, can be differentiated by visual inspection of the C-H stretching region (3100-2800 cm-1) and by using principal components analysis. Bands at 2922, 2852, and 1738 cm-1 assigned to the νasym(CH2 acyl chain lipids), νsym(CH2 acyl chain lipids), and the ester carbonyl band, respectively, increase as the parasite matures from its early ring stage to the trophozoite and finally to the schizont stage. Training of an artificial neural network showed that excellent automated spectroscopic discrimination between P. falciparum-infected cells and the control cells is possible. FT-IR difference spectra indicate a change in the production of unsaturated fatty acids as the parasite matures. The ring stage spectrum shows bands associated with cis unsaturated fatty acids. The schizont stage spectrum displays no evidence of cis bands and suggests an increase in saturated fatty acids. These results demonstrate that different phases of the P. falciparum intraerthyrocytic life cycle are characterized by different lipid compositions giving rise to distinct spectral profiles in the C-H stretching region. This insight paves the way for an automated infrared-based technology capable of diagnosing malaria at all intraerythrocytic stages of the parasite’s life cycle (75). Laser Induced Breakdown Spectroscopy (LIBS). Extensive knowledge exists of the interaction mechanisms between pulsed laser radiation and matter required for LIBS. The technology progress achieved over the last years has opened new fields and industrial applications for LIBS. Remote filament-induced breakdown spectroscopy (R-FIBS) using ultrashort laser pulses was used to measure the carbon/ clay ratios between three graphite composites of different hardness at a standoff distance of 6 m. Measurements using R-FIBS and femtosecond laser-induced breakdown (fs-LIBS) reveal similar selectivity and ability to excite emission. Comparison of the two stand-off techniques with optical microscopy and electron microprobe point detection confirmed the qualitative analysis capability of both femtosecond remote probing techniques. The R-FIBS technique produced more accurate results compared to fs-LIBS due to the intensity clamping nature of the filament ablation source. Measurement of the plasma temperatures for the metallic emission lines (8500 K) and the C2 Swan lines (4500 K) suggest that the plasmas from different microdomains (clay and graphite) are not in equilibrium (76). Near-Infrared. NIR or Near-IR spectroscopy has been used as a standard spectroscopic technique applied to measurement of samples under in situ conditions since the late 1970s. It has been used widely for many industrial applications and most recently in medical assessment of tissue. NIR has been used for nearly 3 decades to monitor pharmaceutical and polymer processing applications. For polymer reactions, oxidation and elimination can be monitored to control quality of the final product. New algorithm approaches are most often applied to NIR spectra, and 4636
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these advances are covered more comprehensively in the Process Chemometrics section of this review. Multivariate calibration models are constructed through the use of Gaussian basis functions to extract relevant information from single-beam spectral data. These basis functions are related by analogy to optical filters and offer a pathway to the direct implementation of the calibration model in the spectrometer hardware. The basis functions are determined by use of a numerical optimization procedure employing genetic algorithms. This calibration methodology is demonstrated through the development of quantitative models in near-infrared spectroscopy. Calibrations are developed for the determination of physiological levels of glucose in two synthetic biological matrixes, and the resulting models are tested by application to external prediction data collected as much as 4 months outside the time frame of the calibration data used to compute the models. The calibrations developed with the Gaussian basis functions are compared to conventional calibration models computed with partial leastsquares (PLS) regression. For both data sets, the models based on the Gaussian functions are observed to outperform the PLS models, particularly with respect to calibration stability over time (77). NMR. The application of NMR to the analysis of natural products has improved through the work of researchers specifically studying nondestructive testing of tomato mechanical damage (78), tomato quality (79), basic food quality (80), and seeds and fruits (81). These advances indicate significant improvements on the use of NMR as a process monitoring technique. Raman Spectroscopy (SERS). Raman spectroscopy provides detailed molecular structure information for in situ analysis using rugged and easily constructed instrumentation. Analytical techniques for rapid and nondestructive measurements are advancing rapidly. Both Raman spectroscopy and near-IR spectroscopy are used for this purpose, and analytical precision and accuracy for these spectroscopic methods are approaching those achieved using traditional laboratory techniques, which often involve sample preparation, separation, and analysis. Surface-enhanced Raman scattering (SERS) was used to measure molecular spectra of living cells. The technique was demonstrated using a nuclear targeting nanoprobe. This nanoprobe is based on peptide functionalized gold nanoparticles for surface-enhancement. The authors probed an original SERS signal from a living cell nucleus by using high-selectivity functionalized gold nanoparticles. The gold nanoparticles conjugated with SV40 large T nuclear localization signal (NLS) peptide successfully enter the cell nucleus after the incubation with HeLa cells and deliver the spatially localized chemical information of the nucleus, as well as the signature of chemicals that intruded subsequently. This new targeted nanoprobe is a nontoxic, biocompatible method for biological research, provided with multiple functions comprising subcellular targeting, intracellular imaging, and real-time SERS detection (82). Surface-enhanced Raman scattering was demonstrated for detection of concentration-dependent spectra for several label-free proteins (lysozyme, ribonuclease B, avidin, catalase, and hemoglobin) for the first time in aqueous solutions. Acidified sulfate was used as an aggregation agent to induce high electromagnetic enhancement in SERS. Strong SERS spectra of simple and
conjugated protein samples could easily be accessed after the pretreatment with the aggregation agent. The detection limits of the proposed method for lysozyme and catalase were as low as 5 µg/mL and 50 ng/mL, respectively. This detection protocol for label-free proteins has combined simplicity, sensitivity, and reproducibility and allows routine qualitative and relatively quantitative detections. Thus, it has great potential in practical highthroughput protein detections (83). Surface Plasmon Resonance (SPR). Increased use of SPR spectroscopy for analysis of proteins, both for research and discovery as well as production and quality control, is becoming more prevalent. Whether applied to the production of proteins or for basic research, this technique is powerful for studying the binding nature of molecules on surfaces. Rapid, sensitive, and accurate detection of analytes present in low concentrations in complex matrixes is a critical challenge. One issue that affects many biosensor protocols is the number and nature of the interferences present in complex matrixes such as plasma, urine, stool, and environmental samples, resulting in loss of sensitivity and specificity. A method was reported for rapid purification, concentration, and detection of target analytes from complex matrixes using antibody-coated superparamagnetic nanobeads (immunomagnetic beads, or IMBs). The surface plasmon resonance (SPR) detection signal from staphylococcal enterotoxin B (SEB) was dramatically increased when the IMBs were used as detection amplifiers. This procedure was used to successfully purify and concentrate SEB from serum and stool samples, then amplify the SPR detection signal. This technique is applicable to measurement of low analyte concentrations in complex biological samples (84). Saliva provides a useful and noninvasive alternative to blood for many biomedical diagnostic assays. The level of the hormone cortisol in blood and saliva is related to the level of stress. We present here the development of a portable surface plasmon resonance biosensor system for detection of cortisol in saliva. Cortisol-specific monoclonal antibodies were used to develop a competition assay with a six-channel portable SPR biosensor designed in our laboratory. The detection limit of cortisol in laboratory buffers was 0.36 ng/mL (1.0 nM). An in-line filter based on diffusion through a hollow fiber hydrophilic membrane served to separate small molecules from the complex macromolecular matrix of saliva prior to introduction to the sensor surface. The system will also be useful for a wide range of applications where small molecular weight analytes are found in complex matrixes (85). Terahertz Spectroscopy. Terahertz or far-infrared spectroscopy has been demonstrated recently as a powerful imaging technique with potential macroimaging of materials and personnel related to process and security applications. A variety of instrumentation and data processing techniques are in current development. Terahertz spectroscopy has been applied to the spectra of polymorph forms. Rigid molecule atomistic lattice dynamics calculations have been performed to predict the phonon spectra of the four polymorphs of carbamazepine, and these calculations predict that there should be differences in the spectra of all four forms. Terahertz spectra have been measured for forms I and III, and there are clearly different features between polymorphs’
spectra that are accentuated at low temperature. While carbamazepine adopts the same hydrogen bonded dimers in all of its known polymorphs, the calculations show that differences in packing arrangements of the dimers lead to changes in the frequency ranges for each type of hydrogen bond vibration, giving a physical explanation to the observed differences between the spectra. While harmonic rigid molecule lattice dynamics shows promise for understanding the differences in spectra between polymorphs of organic molecules, discrepancies between the observed and calculated spectra suggest areas of improvement in the computational methods for more accurate modeling of the dynamics in molecular organic crystals (86). X-ray. The development of new materials from which to construct controlled chemical-release systems has been an active area of research for the past 4 decades. Using XPS analysis, researchers have demonstrated that graphite powder and multiwalled carbon nanotubes (MWCNTs) covalently derivatized are important new micro- and nanoscale materials for use as voltammetrically controlled chemical-release reagents in applications where the small size of the material is advantageous. It is envisaged that derivatives of these materials could be used in vivo in a wide range of areas including medical diagnosis and targeted drug-delivery systems as well as for in vitro applications such as analytical chemical sensor technology, and industrial process monitoring and control. Another advance has been in micro-XRF. By using an excitation energy of 27.0 keV, synchrotron radiation-induced micro-X-ray fluorescence (SR-µXRF) is employed to extract information regarding the composition and distribution of Cd-bearing phases in municipal solid waste (MSW) and biomass fly ashes. The significance of observation is based on statistics of totally more than 100 individual MSW and biomass fly ash particles from a fluidized bed combustion (FBC) plant. Cd concentrations in the parts per million range are determined. The observations are condensed into a schematic mechanism for Cd adsorption on the fly ash particles (87). MASS SPECTROMETRY MS is gaining widespread use and acceptance in nearly all areas of analytical chemistry, especially in medical research and in drug discovery for pharmaceutical preparations. The determination of the molecular structures of metabolites is an essential part of the early pharmaceutical drug discovery process. Understanding the structures of metabolites is useful both for optimizing the metabolic stability of a drug as well as rationalizing drug safety profiles. MS is particularly useful during synthesis and identification of drug molecular species. MALDI-MS. Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) is reported for quantitative measurements from a variety of small-volume biological samples. Cell-tocell signaling peptides play important roles in neurotransmission, neuromodulation, and hormonal signaling. Significant progress has been achieved in qualitative investigations of signaling peptides in the nervous system using single cell measurements. This work describes several methods for quantitative microanalysis of peptides in individual Aplysia californica neurons and small pieces of tissue. Stable isotope labeling with d0- and d4-succinic anhydride and iTRAQ reagents have been successfully adopted for relative quantitation of nanoliter volume samples containing the Aplysia insulin Cβ peptide. The method of standard addition Analytical Chemistry, Vol. 81, No. 12, June 15, 2009
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permits absolute quantitation of the physiologically active neuropeptide cerebrin from small structures, including nerves and neuronal clusters, in the femtomole range with a limit of detection of 19 fmol (88). Fourier Transform Ion Cyclotron Resonance-Mass Spectrometry (FTICR MS). Atmospheric pressure photoionization (APPI) FT-ICR MS has significantly contributed to the molecular speciation of petroleum. However, a typical APPI source operates at 50 µL/min flow rate and thus causes a considerable mass load to the mass spectrometer. The recently introduced microchip APPI (µAPPI) operates at much lower flow rates (0.05-10 µL/ min) providing decreased mass load and therefore decreased contamination in the analysis of petroleum by FTICR MS. In spite of the 25 times lower flow rate, the signal response with µAPPI was only 40% lower than with a conventional APPI source. It was also shown that µAPPI provides very efficient vaporization of higher molecular weight components in petroleum analysis (89). Proton-Transfer Reaction-Mass Spectrometry (PTR-MS). PTR-MS allows quantitative determination of volatile organic compounds in real-time at concentrations in the low part per trillion range, but cannot differentiate isomers or isobaric molecules, using a conventional quadrupole mass filter. The application of linear quadrupole ion trap (LIT) mass spectrometry in combination with proton-transfer reaction chemical ionization was used to provide the advantages of specificity from MS/MS. A commercial PTR-MS platform composed of a quadrupole mass filter with the addition of end-cap electrodes enabled the mass filter to operate as a linear ion trap. The rf drive electronics were adapted to enable the application of dipolar excitation to opposing rods, for collision-induced dissociation (CID) of trapped ions. This adaptation enabled ion isolation, ion activation, and mass analysis. The utility of the PTR-LIT was demonstrated by distinguishing between the isomeric isoprene oxidation pair, methyl vinyl ketone (MVK) and methacrolein (MACR). The CID voltage was adjusted to maximize the m/z 41 to 43 fragment ratio of MACR while still maintaining adequate sensitivity. Linear calibration curves for MVK and MACR fragments at m/z 41 and 43 were obtained with limits of detection of approximately 100 ppt, which should enable ambient measurements. Finally, the PTR-LIT method was compared to an established GC/MS method by quantifying MVK and MACR production during a smog chamber isoprene-NOx irradiation experiment (90). PROCESS CHEMOMETRICS Chemometrics and Multivariate Analysis. As in the previous review (91), breakthroughs and advances in the fields of chemometrics, multivariate statistics, and process monitoring and control are highlighted and trends within the field are evaluated. There were thousands of citations across these fields over the past 2 years. This should come as no surprise since disciplines related to computer science, informatics, and all engineering disciplines are facile in the use of multivariate analysis methods for both basic research and for applied science. We have attempted to focus on papers that provide the reader with a broader introduction to topics and to application areas that provide valuable entry points into a larger body of literature. However, it was necessary to omit many interesting and valuable application papers due to limitations in the number of references that can be cited in this review. As a result, we are constrained in providing in4638
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depth coverage of batch modeling and multivariate statistical process control, topics that many consider to be the heart of process chemometrics. The articles that are highlighted in this section were selected due to the unique nature of many of the mathematical methods employed and the specific approaches taken by individual research groups when applying a particular methodology of chemometrics to a problem in process control or monitoring. During this reporting period, a large number of review articles on chemometrics and its applications to process control and monitoring have been published. In a very readable and comprehensive review, Ulmschneider (92) discusses the basic concepts and impact of chemometrics on process analytical technology. In a popularizing article, Wold (93) explains how chemical instrumentation and chemometrics provides a formidable toolbox for investigating and analyzing data from chemical processes with the characteristic patterns relating to classes, trends and other relations uncovered in the data interpreted by comparison with patterns from known and well understood systems and processes. Johnson (94) in a review of multivariate data analysis and PAT discusses how four of the major biotech companies, Amgen, Genentech, Wyeth Biotech, and Medimmune, are using chemometrics to solve problems encountered in biotech processing. Roggo (95) in a review on chemometrics for pharmaceutical process monitoring focuses on the chemometric techniques used in pharmaceutical NIR applications. The use of Raman spectroscopy and chemometrics for PAT in pharmaceutical process monitoring is the subject of a review by Barnes (96). Several other important reviews on the application of more specific chemometric techniques to problems in PAT were also published during this period. Goodacre (97) discusses minimum reporting standards for multivariate data with respect to other collected experimental data. Experimental design, data preprocessing including outlier detection, row and column scaling, and application of validation methods to the data following classification or multivariate regression are discussed in the context of the chemometric analysis. Rius (98) provides an overview of multivariate curve resolution and its limitations to evolving systems in PAT. This review summarizes most of the applications of multivariate curve resolution to reacting systems that have been published between January 2000 and June 2007. Two reviews (99, 100) focusing on the emergence of chemical (e.g., near-infrared, infrared, and Raman) imaging systems to complement chemical identification by acquiring spatially located spectra that enable visualization of chemical compound distributions in pharmaceutical processes were published. Each review is devoted to the spectroscopic methods used to collect the data and the chemometric techniques used to extract the information of interest from imaging data. The quality and authenticity of food products, which are two important issues in the food chain, are the subjects of three reviews (101-103) during this period. In each review, the importance of chemometric methods such as principal component analysis, discriminant analysis, cluster analysis, canonical variates, and factor analysis are discussed. Specific application areas are highlighted in each review. Batch Modeling and Multivariate Statistical Process Control. Amigo and co-workers (104) describe the advantages of coupling parallel factor analysis to multiwavelength fluorescence
spectroscopy as a monitoring and real time control tool. Processes measured under normal operating conditions were used to develop a calibration model with the residuals of the model used in combination with multivariate statistical process control to establish control limits, which in turn were used to monitor new batches in real time. Multiway locality preserving projections (MLLP), a dimensionality reduction technique for preserving the neighborhood structure of a data set is described (105) and compared to multiway principal component analysis. MLLP outperformed conventional multiway principal component analysis for data with high signal-to-noise. Neighborhood preserving embedding (NPE) was also used to preserve the local neighborhood structure of the data for two-way analyses of the data (106). NPE was able to find more meaningful information in high-dimensional batch processing monitoring data than PCA. Using multiblock methods, Hoskuldsson (107) divided the X-matrix into two data blocks, NIR data and process variable data, to determine the effect of a subprocess. With the use of the multiblock approach, more information on the process was obtained than if all of the data were treated as a single block. By application of wavelet texture analysis to raw image data of paper formation to compute a wavelet signature for each image, it was possible to ascertain the quality of the paper being formed (108). Principal component analysis (PCA) of the signatures confirmed the different formation quality levels which were defined a priori after visual inspection of the paper products. A process control framework based on this PCA description of the data was used to monitor paper formation quality with the results validated using receiver operator characteristic curves and confirmed with a Monte Carlo simulation study using subimages of the original data. Many multivariate statistical process control models are derived using partial least-squares to aid in product transfer and scale up. In one study, Garcia-Munoz (109) built a calibration model in parallel with the development of the manufacturing process itself. Each time when the PLS model was tested using NIR data from a new batch run, an unexplained bias was observed which was attributable to the NIR signal itself. Data on the processing conditions collected for all batches was included in a joint PLS model with the loadings and scores containing information about the observed cause of the drift in the previous calibration models. In another study (110), a two stage PLS methodology is used to monitor processes that are known to be affected by sources of variation that confound or mask more subtle process changes that are of particular interest. In the first stage of this two stage algorithm, the confounding variation in the data are removed through the application of the PLS filter. In the second stage, latent variables are extracted from the filtered signal. The two-state PLS algorithm, which is compared to conventional PLS and orthogonal signal correction PLS, is shown to be better at detecting and locating the sources of subtle process changes. In a third study, Trygg (111) describes two methods for significance testing for PLS and orthogonal signal correction PLS based on an analysis of variance of the cross validated residuals of Y. The two methods perform well when PLS and orthogonal signal correction PLS perform well. PLS methods generally do not perform well in multivariate process performance studies involving nonlinear processes. During this period, two nonlinear multiscale MSPC chemometric methods, which appear promising,
were published in the literature. One approach known as principal component curves (112) was used to develop a model from near IR and Raman data for online monitoring of 15 batch emulsion reactions for monomer concentration and polymer content. The other approach uses kernel PCA (113) that not only captures nonlinear variation between variables but also reduces the dimensionality of the data. Kernel PCA is applied to reconstructed data obtained from performing the wavelet transform and the inverse wavelet transform sequentially on the measured data. A simulation study performed on a continuous stirred tank reactor processor using kernel PCA outperformed current approaches. Much of the chemical literature on batch modeling and multivariate statistical process control focused on novel and not so novel applications. A few of the more interesting applications are discussed here. MacGregor (114) used PLS to analyze data from an online vibrational sensor to obtain real time prediction of product texture in a commercial snack food process. The data was obtained using an accelerometer to record the vibrational signature generated by the snack food falling onto the metal surface. This data was then used to model the textured properties of the snack food. High-performance liquid chromatography was used to study a continuous process for 83 h. With the use of evolving PCA, the normal operating condition region of the process was identified. A major challenge encountered by Brereton and co-workers (115, 116) was to develop a peak table as the process evolves, which is dynamically updated as new peaks are detected after the normal operating condition region. The approach involving the use of an unlocked peak table to detect out of control samples generally performed better than diagnostics based on using only peaks identified in the normal operating condition region. Pharmaceutical Chemometrics. Few novel chemometric methods for pharmaceutical process control and monitoring were published during this reporting period. Instead the chemical literature on pharmaceutical process control focused on applications. Some of the more important applications are reported here. Terahertz spectroscopy and PLS or principal component regression have been applied to quantitate both active ingredients and excipient concentrations of tablets (117). The predicted concentrations from the multivariate models agreed well with nominal concentrations demonstrating the feasibility of integrating terahertz spectroscopy with PAT via chemometrics. Paracetamol, ibuprofen, and caffeine have been determined in tablets using UV visible absorbance between 200 and 400 nm at an interval of 1 nm in methanol-0.1 M HCl (118). Multivariate calibration models were developed using PLS, genetic algorithms coupled with PLS (GA-PLS), and principal component-artificial neural networks. GA-PLS performed the best due to wavelength selection without loss of prediction capacity. Near-infrared imaging coupled to selfmodeling curve resolution (119) was used to obtain concentration profiles of both the active ingredient and excipient ingredient in pharmaceutical tablets. Concentration profiles obtained by selfmodeling curve resolution revealed that homogeneous distributions of the active ingredient depended strongly on the grinding time, which also played a key role in the sustained release of the active ingredient. With the use of Raman and near-infrared data, it was possible to develop correlations between pharmaceutical properties such as hardness, porosity, and crushing strength Analytical Chemistry, Vol. 81, No. 12, June 15, 2009
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(120). PLS models generally gave very good fits for each of these physical properties. Pharmaceutical PAT. Near-infrared applications require multivariate calibration chemometrics and sophisticated data preprocessing mathematics. This technique has profited considerably from the use of flexible and robust fiber-optical probes. So far, a comparable technique for mid-IR was not available due to low stability and lack of robustness of the fibers. Recent research reports the use of a newly developed miniaturized diamond ATRprobe with high chemical resistance and pressure resistance based on robust fiber optics. The routine and convenient application in a glovebox to highly air- and oxygen-sensitive reactions on a milliliter scale is reported, as well as the monitoring of a solventless reaction on a liter scale (121). AI or Artificial Intelligence. Implementation of automation and process analysis for real-time measurements requires a certain integrated intelligence to apply calibration, operation, and control to systems. AI has provided such technological adaptation for intelligent systems developments. Rapid, objective techniques for monitoring the ripening process of fermentation products are of interest in the food industry. An electronic-nose (e-nose) technology offers an easy to use, more economical, and automated system incorporating artificial intelligence and is easily used for quality screening. A review of fuzzy set theory and fuzzy logic was published over the review period. Fuzzy modeling and real applications of fuzzy sets are focused into four major topics: philosophy and background mathematics of fuzzy set theory and fuzzy logic, robust fuzzy statistics and regression, fuzzy clustering, ecology modeling and fuzzy multivariate data analysis. Fuzzy techniques as other artificial intelligence techniques have seen increasing usage in analytical chemistry in the past decades. It is known that fuzzy approaches are ideally suited for those areas in which imprecise or incomplete measurements are an issue. Its primary application was the mining of large data sets. Considerable literature describing the use of artificial neural networks (ANNs) has evolved for a diverse range of applications such as fitting experimental data, machine diagnostics, pattern recognition, quality control, signal processing, process modeling, and process control, all topics of interest to chemists and chemical engineers. Because ANNs are nets of simple functions, they can provide satisfactory empirical models of complex nonlinear processes useful for a wide variety of purposes. This article describes the characteristics of ANNs including their advantages and disadvantages, focuses on two types of neural networks that have proved in our experience to be effective in practical applications, and presents short examples of four specific applications. In the competitive field of modeling, ANNs have secured a niche that now, after 2 decades, seems secure (122). INFORMATICS Cheminformatics. Cheminformatics (also known as chemical informatics) is the general use of computer techniques useful for solving chemistry related problems. Web-based molecular processing tools installed on corporate Intranets bring cheminformatics and molecular modeling capabilities directly to the desks of synthetic chemists, giving them direct access molecular structural and property visualization data and analysis. This process has dramatically improved efficiency of the drug design 4640
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and development process. User-friendly tools that use a standard Web browser as an interface allow access to a broad range of expert molecular processing tools, without the need for specialized expertise in their use. Web-based tools offer many advantages for processing chemical information, most notably ease of use and high interactivity. Therefore more and more pharmaceutical companies are using Web technology to deliver sophisticated molecular processing tools directly to the desks of their chemists, to assist them in the process of designing and developing new drugs. Natural products (NPs) have been optimized in a very long natural selection process for optimal interactions with biological macromolecules. NPs are therefore an excellent source of validated substructures for the design of novel bioactive molecules. Various cheminformatics techniques can provide useful help in analyzing NPs, and the results of such studies may be used with advantage in the drug discovery process. In the present study, a method is described to calculate the natural product-likeness score, a Bayesian measure which allows for the determination of how molecules are similar to the structural space covered by natural products. This score is shown to efficiently separate NPs from synthetic molecules in a cross-validation experiment. Possible applications of the NP-likeness score are discussed and illustrated on several examples including virtual screening, prioritization of compound libraries toward NP-likeness, and design of building blocks for the synthesis of NP-like libraries (123). PROCESS CONTROL Automation of Processes and Analytical Systems. The use of automated sample processing, analytics and screening technology for profiling absorption, distribution, metabolism, and excretion (ADME), and physicochemical properties, early in the drug discovery process, is becoming more widespread. The use and application of these technologies is both diverse and innovative. High-throughput screening (HTS) technologies have been utilized enabling the profiling of an increased number of compounds emerging from the drug discovery process. Although the drivers for using these technologies are common, different approaches can be taken. Control Systems. Safe, efficient, and economical operation of chemical processes are ever more dependent in the use of online analyzers. The use of analytical measurements of component properties in near real-time for process control during manufacturing is becoming more common. The combination of online analyzers and advanced control technologies holds an enormous economic potential. As a result, the number of existing applications is growing steadily. Process Control Algorithms. Advances in process control algorithms and technical approaches continue to advance. An automated reactor system for a detailed performance evaluation of gas-phase heterogeneous oxidation catalysts that utilizes a parallel array of six fixed microreactors called the multiple automated reactor system, or MARS, has been described. The key MARS components include a gas manifold that safely generates a light hydrocarbon oxidation feed composition, an array of six fixed-bed microreactors with dedicated components for control of individual reactor feed gas flow rates and temperatures, an integrated gas sampling and gas chromatography system for online analysis of feed and product gas compositions, and a
process automation control package based on process logic controller technology. The addition of one or more liquid feed components, such as steam or organometallic catalyst surface modification agents, is also possible through a dedicated liquid feed vaporizer subsystem. The automation package contains all of the elements needed for logging of process sensors, monitoring of all process alarms, control of all process variables, interlock sequencing, and communication between the operator and automation hardware through a human-machine interface. These features allow a user-defined catalyst testing protocol to be downloaded from the automation so that the system can safely operate 24/7 in an unattended mode (124). FLOW INJECTION ANALYSIS (FIA) Online dialysis performed in a flow injection analysis system has been integrated with a capillary electrophoresis (CE) system via a specially designed interface. Samples are continuously pumped into a dialysis unit and the outgoing acceptor stream containing the analytes is allowed to fill a rotary injector in the FIA part of the system. A discrete, representative volume of the acceptor stream is injected into an electrolyte stream which continuously passes through the FIA-CE interface into which the end of a capillary has been inserted. An infinitesimal fraction of the injected acceptor plug is introduced electrokinetically when it passes the end of the capillary. Multiple sample injections are possible in one electrophoretic run, and the entire analytical procedure can easily be mechanized. The repeatability is in the range 1.6-3.3% (n ) 7). A wide range of real samples with complicated matrixes (milk, juice, slurry, liquors from pulp and paper industry) was successfully analyzed without any off-line pretreatment using the fully mechanized system (125). ULTRASOUND Ultrasonic devices are gaining the confidence of analytical chemists who use them for helping in steps ranging from sampling through to detection. From the most basic use for cleaning surfaces to the facilitation of methods for analyses of process parameters, particularly those involved in sample preparation. A variety of simple sensors for use in ultrasound applications have been developed. A chemical sensor is described that can detect the frequency of ultrasound. Exposure of aqueous n-alkyl sulfate or sulfonate surfactant solutions to high-intensity ultrasound results in the formation of secondary carbon-centered radicals. The yield of these radicals reaches a maximum plateau, the magnitude of which is limited by the dynamic ability of the surfactant to accumulate at the rapidly oscillating gas-solution interface of cavitation bubbles. For this reason, the maximum plateau yield observed following sonolysis of sodium butane sulfonate solutions compared to that of sodium dodecyl sulfate solutions (i.e., CHSBSo/ CHSDS) was greater than 1. Interestingly, it was found that the CHSBSo/CHSDS ratio had a linear dependence on the ultrasound frequency. The effect can best be described in terms of the dynamic surface tension of surfactants in relation to the influence of ultrasound frequency on the lifetime of the gas-solution interface of sonochemically active cavitation bubbles (126).
MISCELLANEOUS SENSORS Hand-Held Sensors. Microfabrication techniques are providing the technological means for producing accurate and precise battery powered and rugged analytical systems. These systems are becoming more commonplace due to the necessity of improved field monitoring of hazards and threats to security and safety. They are also applicable for field portable quality and manufacturing process assessment applications. A paper provides a demonstration on how to prepare microfabricated columns (microcolumns) for organophosphonate and organosulfur compound separation that rival the performance of commercial capillary columns. Approximately 16 500 theoretical plates were generated with a 3 m long OV-5-coated microcolumn with a 0.25 µm phase thickness using helium as the carrier gas at 20 cm/s. Key to the advance was the development of deactivation procedures appropriate for silicon microcolumns with Pyrex tops. Active sites in a silicon-Pyrex microcolumn cause peak tailing and unwanted adsorption. FT-IR analysis shows that exposure to PMP forms a bond to the stationary phase that deactivates the active sites responsible for organophosphonate peak tailing. These microfabricated columns have high potential for a variety of separation applications (127). A miniature, hand-held mass spectrometer, based on the rectilinear ion trap mass analyzer, has been applied to air monitoring for traces of toxic compounds. The instrument is battery-operated, hand-portable, and rugged. Its use is projected to be for public safety, industrial hygiene, and environmental monitoring. Gaseous samples of nine toxic industrial compounds, phosgene, ethylene oxide, sulfur dioxide, acrylonitrile, cyanogen chloride, hydrogen cyanide, acrolein, formaldehyde, and ethyl parathion, were tested. A sorption trap inlet was constructed to serve as the interface between atmosphere and the vacuum chamber of the mass spectrometer. After selective collection of analytes on the sorbent bed, the sorbent tube was evacuated and then heated to desorb analyte into the instrument. Sampling, detection, identification, and quantitation of all compounds were readily achieved in times of less than 2 min, with detection limits ranging from 800 ppt to 3 ppm depending on the analyte. For all but one analyte, detection limits were well below (3.5-130 times below) permissible exposure limits. A linear dynamic range of 1-2 orders of magnitude was obtained over the concentration ranges studied (sub-part per billion by volume to part per million by volume) for all analytes (128). Jerome (Jerry) Workman, Jr. is Director of Measurement Systems at Luminous Medical Inc. in Carlsbad, California. This Process Analytical Chemistry review article constitutes the seventh in this series he has coauthored since 1995. In his career, Workman has focused on molecular and electronic spectroscopy, process analysis, and chemometrics. He has published widely, including numerous tutorials, scientific papers and book chapters, individual textbook volumes, software programs, and patents/ inventions; he has received several key awards for this work. Melvin V. Koch is Executive Director of the Center for Process Analytical Chemistry (CPAC), at the University of Washington in Seattle, an industry/university/government consortium. He received his B.A. in Chemistry and Mathematics from St. Olaf College, MS, in biochemistry and Ph.D. in Organic Medicinal Chemistry from the University of Iowa. Dr. Koch worked for The Dow Chemical Company in process research and analytical chemistry, achieving the level of Global Director of Analytical Sciences. He is active in coordinating developments in the field of process analytical technology (PAT) between industry, government laboratories, and academia. Dr. Koch has served recently on the FDA advisory committee to the Office of Pharmaceutical Sciences. Analytical Chemistry, Vol. 81, No. 12, June 15, 2009
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Barry K. Lavine is an Associate Professor of Chemistry at Oklahoma State University in Stillwater, OK. He has published approximately 90 papers in chemometrics and is on the editorial board of several journals including the Journal of Chemometrics, Microchemical Journal, and Chemoinformatics. He is the Assistant Editor of Chemometrics for Analytical Letters. Lavine’s research interests encompass many aspects of the applications of computers in chemical analysis including pattern recognition, multivariate curve resolution, and multivariate calibration using genetic algorithms and other evolutionary techniques. Ray W. Chrisman is president and chief scientist at Atodyne Technologies, LLC, Ann Arbor, Michigan 48105, a technology development and commercialization firm focused on rapid characterization technologies and their utilization in process analytical chemistry. He received his B.S. from Manchester College and his Ph.D. in Inorganic Chemistry from Purdue University. He retired from The Dow Chemical Company after a career in R&D in Analytical Chemistry and Chemical Sciences. He is a consultant at BEST Energies, a biofuels company, a visiting Scholar at the Center for Process Analytical Chemistry, CPAC, an advisor at MATRIC, a research institute, and a member of the Purdue University Chemistry Department Advisory Committee.
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