Waters Symposium: Ion Selective Electrodes
waters symposium: ion selective electrodes
The Seventies—Golden Age for Ion Selective Electrodes Jaromir Ruzicka Department of Chemistry BG-10, University of Washington, Seattle, WA 98195-1700 The Waters Symposium offers a unique opportunity to investigate the tortuous, often problematic, yet fascinating relation between Academe and Industry as they interact on the common ground of advanced research. The topic of this year’s symposium, “Ion Selective Electrodes”, shares with the topics of previous symposia several characteristic features: the interaction between academic and industrial partners, their differences stemming from different goals, the importance of serendipity, the genius of the minds of those who exploited the unexpected, the ill fate of true findings that were not recognized or not acknowledged, and claims which, although not based on reality, were diligently pursued. It is a great privilege to be invited to give this account, but since I cannot hope to provide a fair view of this complex field, a disclaimer is appropriate. What will follow is the personal view of a very minor player in this field, necessarily biased. This is not an excuse but an explanation: if we all wandered through a forest and were to describe a certain tree, our accounts would be different, because we not only arrived from different viewpoints, but also at different times. Fortunately the detailed history of ISE as seen by others is available: the paper by Thomas (1), an account by Frant (2), presentations at the recent symposium in Cardiff (3), and monographs on this subject (4, 5) weave a rich and detailed tapestry of this area of scientific research.
Ion selective electrodes are only a small part of the much broader electroanalytical technique termed potentiometry. As its name implies, the method is based on measurement of an electrode potential that is formed at the interface between a solution and an electrode surface, the aim of the potentiometric technique being to assay the quantity or activity of an analyte in that solution. Next year it will be 100 years since the technique was first used by Nernst to measure the acidity of a solution by means of a hydrogen electrode (6). Discussing ISEs against the background of this entire period (Fig. 1) allows us the gain perspective and to recognize how much (or how little) has withstood “the acid test of time”. The need to quantify the degree of acidity became more pressing as chemistry, physiology, and brewing grew in scope during the early years of this century. Since the hydrogen electrode was so obviously impractical, many other methods for estimating acidity were tried, such as the quinhydrone electrode or antimony electrode, although the foundation of the correct approach—the glass electrode—was laid already in 1906 by Cremer (7). Soon afterwards, Haber and Klemensiewicz (8) (the latter doing most of the work [9]) improved the glass electrode to the point where it became of practical interest. This achievement alone, however, would not have been enough to solve the problem of the exact measurement of the acidity of solutions. There
CREMER
Figure 1. The milestones in development of potentriometry and ion-selective electrodes: (a) the devices, (b) the pioneers, (c) the beginnings, and (d) the golden age.
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were two additional essential ingredients: definition of the units to be measured, and availability of a reliable instrument that would provide reproducible readout. It is significant that while the glass electrode originated from academe, the other two components originated from industry. Sorensen, working for Carlsberg brewery in Copenhagen, proposed the pH scale because he needed to define the influence of acidity on numerous enzymatic reactions (5). Beckman designed and commercialized the first pH meter in the U.S.A. in 1935 (10). Interestingly, instrument manufacturing was already a close race in those early days; Radiometer in Denmark introduced its own electronic pH meter at about the same time (11). One can only speculate that both companies were inspired by the work of Elder and Wright, published five years previously (12). In summary, the formula for successful introduction of ISE technology was worked out already in the thirties: (i) cooperation between academe and industry aiming at development of new technology and (ii) integration of concepts of solution chemistry (pH buffers), electrochemistry (the electrode), and electronics (the meter). In this way the need was satisfied and potentiometry became a “mature field” focused on pH measurement, at that time a widely practiced and very useful field of potentiometric titration. It is now accepted that the era of ISEs was initiated through the theoretical work of Nikolski and Schultz (13), which was further expanded by Eisenman (14). Indeed, the Eisenman–Nikolski equation is the basis of modern ISE theory and of the selectivity concept, although inevitably, as the ISE field expanded, it became the subject of revision and critique—a topic to which we shall return later in connection with the IUPAC definition of selectivity coefficient (15). Yet as we see in retrospect, it was the need to measure activity of sodium and potassium in biological fluids for the purpose of physiological research that led to the search for glass of a composition that would allow construction of a sodiumsensitive electrode. Eisenman demonstrated the link between the (troublesome) sodium error of the pH electrode and the central role of the ion exchange mechanism, thus focusing on the mechanism of the charge transfer process across the membrane surface (14, 16). This work opened the field to a rational search for new electrode materials, and its importance can be appreciated against the background of previous largely unsuccessful attempts to create potentiometric devices that would measure ionic species selectively. The pioneering work of Tendeloo (17) and Kolthoff (AgCl disk [18]) and even later attempts by Pungor (19) to produce halide selective electrodes are often quoted as examples of early attempts to make ISEs work. Yet in this context it is only fair to point out that silver wires covered by AgCl, AgBr, AgI, or Ag2S had been used routinely as both indicator and reference electrodes since the early ’30s. Also, silver wires covered with sulfur-containing organic compounds were at that time used as indicator electrodes in potentiometric titrations (20) and for direct potential measurements to estimate solubility products (21). Therefore, making a membrane of silver halides was not likely to inspire further research in the area later known as ISE. The breakthrough came in the ’60s when Ross, working for the newly founded Orion Company (2), invented an entirely new concept of the liquid membrane electrode—and the calcium electrode (22, 23) attracted immediate attention. His and Frant’s work on the fluoride electrode (24), shortly followed by other liquid membrane
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ISEs and a variety of gas sensors, had an electrifying effect on both academe and industry, albeit for different reasons. The interest of the electroanalytical community had been previously focused towards polarography and voltammetry—fields of considerable maturity. Therefore the opening of an unexpected new avenue of research attracted immediate attention. Indeed, in following decades, academic centers of electrochemical research such as the schools founded by Heyrovsky (Czechoslovakia), Shikata (Japan), Kemula (Poland), and Pungor (Hungary) yielded a considerable output on the theme of ISE, comprising a large number of papers and meetings dealing with both theory and practice. The interest of industry was application-driven: fluoridation of drinking water created a need for a rapid and reliable fluoride assay, which before the advent of F-ISE involved tedious distillation followed by unreliable colorimetry. The field of clinical chemistry, specifically blood gas and electrolyte measurement, was in dire need to measure—in addition to pH and oxygen—potassium, sodium, calcium, carbon dioxide, and hopefully also magnesium and even phosphate. With the exception of the last species, these needs were eventually fulfilled by ISE technology, creating a market with sales of about 5000 clinical analyzers per year (11). This combined intellectual and economic challenge provided an impetus that created a vigorous, exciting research field, in which major advances were achieved during the ’60s. It blossomed further in the ’70s, when the largest number of papers were published, numerous national and international meetings were held, and major monographs were authored by leading workers from the field (25–28). Also during this decade a series of symposia on ISE, held in Hungary over the next 10 years, was initiated (e.g., 29). In industry, a fierce competition between leading companies (Corning, Beckman, Radiometer, Phillips, Metroohm, Radelkis) took shape, resulting in numerous patents and occasional lawsuits, of which one dealing with the potassium electrode was rather unfortunate. On a positive note, many new instruments and electrodes were marketed, inspired by the spectacular success of the Orion Company, which was the undisputable leader in this field. Also during the ’70s, at least two very important developments took place. In England, Moody and Thomas invented a practical support for liquid membrane electrodes—the PVC membrane (30). This advance alone made all liquid membranes practical and demonstrated that polymerizable materials can indeed serve as a reliable backbone for ISE membranes. Prior to their work the only polymerizable material of some utility was silicone rubber (31), which never quite fulfilled the expected function. The continuing work of Thomas (1) led to wide use of homemade as well industrially produced ISEs, thus allowing extensive use of these devices worldwide— even in countries and laboratories with limited resources. In this way ISE technology and research became widely practiced, an important aspect of training and education in instrumental analysis. Introduction of PVC as a membrane material led to further simplification of ISE construction. H. Freiser proposed the “coated wire electrode” (CWE) comprising a Pt wire coated by a PVC layer that served as a membrane. This bold approach disposed of both the inner reference solution and the reference electrode, and was consequently subjected to criticism from both theoreticians and practitioners because CWEs were subject to drift. Further development of the CWE, however, led to introduction of inner redox solid
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Waters Symposium: Ion Selective Electrodes
state reference systems, which made these devices more reliable. The second important development took place in Switzerland, where Simon discovered the suitability of polypeptides as electroactive materials and successfully pursued research on this entirely new group of electroactive ligands, the so-called neutral carriers. His initial work with Stefanec (32, 33) was focused on naturally occurring materials, nonactins, that were known to facilitate the transport of alkali metal ions across the lipid membranes. This work led to discovery of the valinomycin electrode for potassium, the ISE of unprecedented selectivity. The lasting impact of this research work can be judged by the fact that the K-ISE in a PVC matrix is now the workhorse of all clinical analyzers marketed today. Working in academe, Simon led the most significant research team in Europe, which during the many years of its existence conceptualized, designed, and synthesized a very large number of neutral carriers, the cagelike structure of which was tailored to accommodate target ions according to their sizes (34, 35). In the course of this work, the most successful compound, ETH1001, was discovered (36) and became a basis of the highly selective Ca-ISE, which today is used in many clinical analyzers. (However, Radiometer instruments, which account for one-third of the world market, use Caoctylphenylphosphate [37] in their Ca-ISE.) The pioneering work of Ross and Frant and the exciting presentations summarized in the NBS publication edited by Durst (25) also made their impact in Denmark, where both academic and industrial tradition provided a solid foundation for research in ISE. Recall that it was Sorensen who laid the foundation for the pH concept, and it was therefore natural to consider the concepts of pM and of metal buffers against the background of the work of Bjerrum and Ringbom—the fathers of complexformation chemistry. Therefore it was quite obvious to us (even trivial) that any efficient work on development of ISEs must be carried out while using solutions of well defined pM value—and above all, of sufficient buffering capacity (37, 38). While the analogy with the pH concept was so obvious, the concept of metal buffers was at that time not kindly accepted, because in the ’60s metal ion ISEs (such as copper, lead, cadmium) were promoted as alternatives to atomic absorption measurement and therefore were often calibrated by diluting soluble salts of these metals in distilled water! The literature of that time is replete with embarrassing attempts to obtain low detection limits at these unreproducible dilutions. Curiously, this approach did not seem to invoke an analogy of calibrating the pH electrode with, say, 10-5 N hydrochloric acid. Today, all heavy metal ISEs are part of history, whereas the use of metal buffers is accepted as appropriate (39, 40). This, and the early insight of Frant and Ross into the importance of introducing TISAB buffer for fluoride measurements (41), documents the paramount importance of understanding the interplay between the mechanism of the sensor response and its interaction with the solution to be measured. Curiously, many historical accounts of the development of ISE do not mention the invention of the enzymatic-ISE proposed by Guilbault (42). These devices comprised an ISE electrode sensitive to an ion produced by an enzymatic reaction with the target analyte. Thus, enzyme-ISE was a classical ISE wrapped into an enzyme-containing membrane. These devices inspired an entirely new field of electrochemical biosensors. (The majority of today’s biosensors are, however, amperomet-
ric devices fashioned after the first glucose sensor by Clark [43]). Nowadays there are many applications of ISE. Indeed, it is said (2) that by 1990 more than 7000 papers had been published on this topic. While mostly aqueous matrices have been analyzed, important work was done in nonaqueous media as well. The use of ISE in nonaqueous solvents was recently reviewed by Coetzee (44), whose early study was important because it allowed calibration of glass electrodes in nonaqueous media (45, 46), which in turn allowed optimization of reaction conditions for many organic syntheses. Research on ISEs resulted in numerous spinoffs or leads, some of which had lasting impact on analytical science. For example, the invention of flow injection analysis was initiated while we were trying to establish the speed of response of the so-called air-gap electrode to ammonia, which was generated by injecting ammonium chloride into a stream of sodium hydroxide. In the process of studying this gas-ISE we realized that the integrity of individual injections was preserved, while the speed and reproducibility of the measurement was so remarkable that a new solution-handling technique could be conceptualized (47). Another spinoff of ISE research was development of CHEMFETs (48) and ISFETs (49), microminiaturized devices that attracted immediate attention for two reasons: (i) a potential to be mass produced by microfabrication, and (ii) their presumed compatibility with catheters, which would allow their implantation in vivo. According to Janata (50), There have been many inventions and discoveries in the history of science, that, for a long time, remained ignored despite the fact that they were based on solid principles. It is remarkable then, that the invention of ion sensitive field-effect transistor (ISFET) immediately captured the interest of the scientific and engineering community although the original claim that ISFET can be operated without a reference electrode was fundamentally incorrect.
Indeed, in spite of great expectations for the potential usefulness of these as implantable devices, it was the necessity to combine ISFETs with a reference electrode, which dashed hopes of making these ingenious devices a commercial success. Yet the legacy of this area of ISE research remains active, as we will see later when discussing microfabrication of individual ISEs as well as ISE arrays. The unmistakable sign that a research area is reaching maturity is when IUPAC forms a committee to define new terms and definitions. Interestingly, the topic of ISE selectivity has been discussed and published by IUPAC commissions twice: in 1976 and for the second time in 1995 (15). Initially a view was taken that the entire problem of selectivity can be neatly described by applying a strictly theoretical approach using Nikolski– Eisenman. The first complication occurred when ions of different charges had to be considered. At that stage Buck proposed a more complex equation (51, 52), which, however, assumes a Nernstian response for both primary and interfering ions. However, as time went on and evidence mounted, it became clear that very few, if any, ISEs respond to interfering ions in a Nernstian fashion and therefore a fresh start was needed. At that point the IUPAC commission adopted a pragmatic approach, concluding that a method for establishing selectivity was needed that would be independent of the N-E equation.
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It finally adapted the so-called “matched potential” method, originally suggested by Gadzekpo and Christian (53). In this method, the selectivity coefficient is defined as the activity (concentration) ratio of the primary ion and the interfering ion, which gives the same potential change in a reference solution. Thus the value of the selectivity coefficient is not based on the Nernstian slope, and the charges of ions involved need not be considered. Once again a compromise has been reached in favor of practical considerations. Today ISE is a mature area, the review of which shows which advances “withstood the acid test of time”. Although the promised use of ISE as a tool for trace analysis has never been fulfilled, the advantages of ISEs (reliability, robustness, and ability to measure activity of ions) makes these potentiometric devices irreplaceable in clinical assays and in many bioindustrial applications. Research in this area is still very active, aiming mostly at clinical chemistry, physiology, and biology. The emphasize is on microminiaturization (54) and mass production of disposable devices (55, 56) that are descendants of H. Freiser’s coated wire ISE (57). On the high technology end are microfabricated sensor arrays designed to map analyte distribution on the surface of live organs (58, 59). Search continues for novel electroactive materials, of which Mg-ISE is an example of a long-sought device first researched by Simon’s team and later developed and applied by Lewenstam (60, 61). Natural membrane materials came into focus, such as the neuronal biosensors (62) researched by one of the pioneers in the field of ISE (63). Although 100 years old, many aspects of membrane-based potentiometry, especially its response–selectivity function, are still not fully understood. It is therefore encouraging that novel theoretical insights are being advanced (64) and that new neutral carriers are being synthesized and used by the research team led by Buck (65). And perhaps as a sign of renaissance, the concept of the Kelvin probe is being resurrected (66), attesting to the versatility of potentiometric technique as it resurfaces once again in a novel form. Acknowledgments I am obliged to Ari Ivaska for critical comments and to R. P. Buck, K. Cammann, J. F. Coetzee, H. Freiser, A. Hulanicki, J. Janata, T. S. Light, G. Rechnitz, and J. R. D. Thomas for photographs and other materials. The financial support given by J. L. Waters is gratefully acknowledged. Literature Cited 1. Thomas, J. R. D. Analyst 1994, 119, 203–208. 2. Frant, M. S. Analyst 1994, 119, 2293–2301. 3. The International Symposium on Electroanalysis; Cardiff, Wales, 1994; Analyst 1994, 119(11). 4. Electrochemistry Past and Present; Stock, J. T.; Orna, M. W., Eds.; ACS Symposium Series 390; American Chemical Society: Washington, DC, 1989. 5. Astrup P.; Severinghaus J. W. The History of Blood Bases, Acids and Bases; Mungsgaard Int.: Copenhagen, 1986. 6. Nernst W. Ber. Dtsch. Chem. Ges. 1897, 30, 1547–1563. 7. Cremer, M. Z. Z. Biol. 1906, 47, 562. 8. Haber, F.; Klemensiewicz, Z. Z. Phys. Chem. 1909, 67, 385–431. 9. Dole, M. J. Chem. Educ. 1980, 57, 134. 10. Beckman, A. O. Hexagon 1987, 78(3), 41. 11. Radiometer Annual Report 1994/1995; Copenhagen. 12. Elder, L. W.; Wright, W. H. Proc. Natl. Acad. Sci. U.S.A. 1928, 14, 938.
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