Ionophore-based ISE

A major advance in ionophore-based ISEs is the finding that their detection limits can be lowered from the micromolar range to the nanomolar or picomolar level. Discuss recent developments and the new understanding that led to such dramatic improvements in the detectability. 

Liquid membranes for ionophore-based ISEs contain not only ionophores but also ion exchangers (ionic sites). If no ionic sites are added in the membrane, coextraction or salt extraction of ionophore/primary ion complexes with counterions occurs, thereby causing no charge separation at the interface. 

On the basis of this mechanism, a great number of ionophore-based ISEs were developed. It should also he noted here that polyvinyl chloride (PVC) has been used since the early 1970s to support liquid membranes, and the term plasticized liquid membrane" has been coined to describe these systems. In those days, the addition of ionic sites was not explicitly realized, but instead, impure ionic sites in the PVC (anionic sites) played virtually the same role. However, the membrane including such an impurity does not allow quantitative control of the optimized amounts of ionic sites, and therefore, it was supplemented later by deliberately added ionic sites. 

Combining ionophore-based ISEs with enzymes and antibodies... 

To date, the majority of enzyme-based potentiometric sensors do not involve detection with an ionophore-doped selective membrane and fall outside of the scope of this chapter. The same is also true for most Severinghaus-type gas sensors, where a gas-permeable membrane covers an inner solution in which the gaseous analyte is determined with an ISE. Most Severinghaus-type electrodes use a pH-sensitive glass electrode to monitor the pH of this inner filling solution. However, ammonia has been detected indirectly with an ammonium-selective ionophore-based ISEs upon protonation in that inner solution, and the use of other ionophore-based ISEs for the more selective detection both in enzyme-based and Severinghaus-type ISEs is readily conceivable. 

Another well-developed field of chemical sensors that was originally inspired by ISEs is that of optodes, which differ from ionophore-based ISEs fundamentally in that they do not rely on changes in a phase boundary potential but require after each change of sample a reeqniUbiation that involves a complete exchange of the ionic composition of the optode membrane bulk. In the example shown in... 

Because of the key role of NH4" in various biological processes, the direct measurement of this ion is important for clinical and environmental analyses. Ammonium concentrations in food also provide a measure of freshness. Moreover, various enzymes catalyze the deamination of numerous organic compounds, which makes NH4+ selective ionophores also of interest for enzyme-based ISEs (Section 3.1.7). For all these reasons, there has been a continued interest in the development of ionophore-based ISEs for NH4+. 

While there has been only a limited interest in ionophore-based ISEs for Be " ", Sr " ", and Ba " "," the development of Mg + and Ca + ISEs suitable for measurements in blood samples has been for several decades one of the most competitive topics in the field of ion-selective potentiometry. Success came much faster for Ca + than for the smaller and more hydrophilic Mg +, for which ionophoie-based ISE were finally introduced in clinical analyzers in 1994. This can be at least partially explained by the fact that, as a result of the stronger hydration of Mg +, the use of a hypothetical ionophore that binds Mg + and Ca + equally strong would result in an ISE with selectivity for Ca + over Mg " ". Therefore, binding of Mg + by the ionophore has not only to be selective over Ca +, but it also has to compensate for the difference in the free energies of ionophore-unassisted phase transfer from the aqueous into the sensing membrane. Analogous problems arise in the development of other strongly hydrophilic cations (e.g., Li+) and anions (e.g., sulfate and phosphate). 

Even though the number of transition metal and lanthanide cations is very large, the day seems to be soon approaching when an ionophore-based ISE will have been reported for the detection of every one of these cations. Arguably, with notable exceptions, the overall level of sophistication of the ionophore design used for these sensors has not yet reached the level that it has in the case of the ISEs for alkali and alkaline earth metal cations discussed above. 

In summary, considerable efforts have been spent to show the feasibility of ISEs for organic analytes. While some authors used ionophore-based ISEs to measure organic target analytes in relatively simple samples such as drug tablets that contained besides the analyte only hydrophilic inorganic ions, only very few reports exist on the use of such electrodes for measurements in more complex samples such as blood, saliva, or milk. 

How can we create such a membrane for a wider range of analytes The most successful approach is to use ion-selective liquid membranes (2, 3). The liquid membranes are hydrophobic and immiscible with water, and most commonly made of plasticized poly(vinyl chloride). The selectivity is achieved by doping the membranes with a hydrophobic ion (ionic site) and a hydrophobic ligand (ionophore or carrier) that selectively and reversibly forms complexes with the analyte (Figure 7.1). Whereas the technique has been well established experimentally since the 1960s, it is only recently that the response mechanisms are fully understood. In this chapter, principles of liquid membrane ISEs will be introduced using simple concepts of ion-transfer equilibrium at water/liquid membrane interfaces. Non-equilibrium effects on the selectivity and detection limits will also be discussed. This information will enable practitioners of ISEs to better optimize experimental conditions and also to interpret data. Additionally, examples of ISEs based on commercially available ionophores are listed. More comprehensive lists of ionophore-based ISEs developed so far are available in recent lUPAC reports (4-6). 

Besides hydrophobicity of ions and stability of their ionophore complexes, the concentration and charge of the ionic sites in the membrane phase also affect the ion selectivity of ionophore-based ISEs. This effect was first found for neutral-ionophore-based ISEs (14, 43), then for charge-ionophore-based ISEs (10, 33), and most recently implemented in an equilibrium phase boundary potential model generalized for both systems with primary and interfering ions of any charges and their complexes of any stoichiometries (34). 

When zj I / Hj < zi / Wj, the selectivity can be dramatically improved by optimizing the concentration and charge of ionic sites to satisfy equation (7.3.8). Figure 7.5 shows the effect of anionic sites on the Mg + selectivity of a neutral-ionophore-based ISE as determined by the SSM (14). The selectivity coefficients strongly depend on the membrane concentration of the anionic sites and result in optimum values against most ions with 120 mol% anionic sites relative to the ionophore concentration. With 1 1 complexes between the ionophore and Mg +, a large amount of the free ionophore is available for the ion in the membrane with 120 mol% anionic sites, i.e ionophore-based mechanism. Ca + and... 

More recently, a generalized phase boundary potential model that describes apparently non-Nemstian equilibrium responses of ionophore-based ISEs was developed (46). The model predicts that ionophore-based ISEs can give three types of apparently non-Nemstian... 

The concept of this mixed ion-transfer potential was recently extended to quantify the non-equilibrium responses of neutral-ionophore-based ISEs (48). Figure 7.11 shows the... 

Hydration energies are still important since ion extraction process is involved and it is typically more difficult to design ISEs for hydrophilic ions than it is for hydrophobic ones. On the other hand, it is often a difficult to design selective receptors for large, bulky ions. Consequently, ionophore-based ISEs for potassium and calcium were realized early on, while selective sensors for magnesium, lithium, sodium, and small anions such as chloride, carbonate, and phosphate have been developed more recently or are still topics of current research. Ionophore-based ISEs for bulky anions such as perchlorate are not really known. 

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