Reagents for lithium electrodes and sensors for blood serum analysis
Sensors 2002, 2,
Reagents for Lithium Electrodes and Sensors for Blood Serum
Gary D. Christian
Department of Chemistry, Box 351700, University of Washington, Seattle, WA 98195-1700, USA
Received: 17 April 2002 / Accepted: 25 April 2002 / Published: 18 October 2002
The measurement of lithium in blood serum requires high selectivity since the
blood contains about 140 mM sodium compared to the 0.5-1.5 mM lithium level in manic
depressive patients under treatment with lithium salts. This review traces the development
of optical and potentiometric methods for the selective measurement of lithium in the
presence of sodium. Selectivities of over 1,000:1 are achievable with properly designed
Spectrophotometry, Fluorescence, Sensors, Ion-Selective Electrodes, Crown
Lithium occurs naturally in blood at very low levels, at the parts per billion level (1).
Administration of lithium salts for treatment of manic depressive psychosis (bipolar personality) was
proposed in 1949 (2), and lithium has been used from the 1950’s for the efficient treatment of this
disease (3). Lithium is toxic in high concentrations (4), yet is ineffective for treatment if too low. It is
therefore important to maintain the blood concentration in the 0.5-1.5 mM range (5). The upper level is
near that where toxic symptoms are manifested, and 5 mM concentration may result in death (6). It is
apparent that accurate measurement of lithium in the blood of patients is important to assure adequate
A major challenge in developing sensors for lithium in blood is the fact that blood contains on the
order of 140 mM sodium, i.e., about 100 to 300 times the concentration of lithium to be measured.
1 Presented at the 8th International Symposium on Electroanalytical Chemistry
(8th ISEC), Changchun, China, October 14-16, 2001.
Numerous attempts have been made to develop reagents and ionophores that exhibit high selectivity
for lithium relative to sodium. In spite of the challenges, successful potentiometric and optically-based
sensors have been developed. Similar compounds are often effective for both types of measurement.
The evolution of these developments will be presented.
The colorimetric reagent, Thoron, forms a weak complex with lithium in alkaline acetone/water
solutions, which results in a bathochromic shift of its spectrum. This was used for the determination of
lithium in serum by removing proteins with trichloroacetic acid, and measuring the change in
absorbance at 480nm against the reagent as reference (7). It was necessary to compensate for sodium
and other electrolytes by adding them to the reagent blank.
Crown ethers and cryptands can be designed to achieve high selectivity as ionophores for specific
ions by varying cavity size, conformational flexibility, and different side groups to influence the size of
the metal ion accommodated. TMC-crown formazane was demonstrated to provide a selectivity over
sodium of about 1,400:1 under solution conditions similar to those used with Thoron (8). 14-Crown-4
ethers exhibit the best cavity size for lithium complexation. The formation of 2:1 sandwich-type
sodium crown ether complexes can be inhibited by adding bulky groups to the base crown. Watanabe
et al. (9) synthesized a PMT 14-crown-4 ether containing a bulky pinane and subunits at the ethano
bridge of the crown that exhibited a remarkable selectivity of more than 10,000:1 for lithium over
sodium. A flow-through optical sensor probe was developed by dissolving the crown, and a lipophilic
anionic dye in the protonated form, in an organic liquid and then adsorbing on a pellicular-type ODS
bead to serve as the sensor. Ion-pair extraction of the lithium occurs, which causes displacement of the
proton, turning the color from yellow to red. Up to 0.1 M sodium had no influence on the lithium
signal down to the detection limit of 10-5 M! Lithium was measured directly in 1:10 diluted artificial
A chromophoric small cavity cryptand phenol exhibits a greater than 4,000:1 selectivity for
complexing lithium in an aqueous alkaline solution, with no solvent extraction required (10). It was
successfully used for determination of lithium in blood serum diluted 1:40 with the reagent.
1-8 Dihydroxyanthraquinone was used as a fluorescence agent to determine lithium in deproteinized
serum, in an alkaline acetone-water solution, exhibiting 480:1 selectivity over sodium (11).
Early lithium ion-selective electrodes were based on amide-type ionophores (12-14). Metzger et al.
(15) were able to determine lithium in undiluted serum with a cyclohexyl diamide compound which
had a selectivity of 80:1 for lithium over sodium. Gadzekpo et al. (16) prepared a series of diamide-
based ionophores with pyridine, furan, and dioxanone backbones, while Attiyat and coworkers (17)
synthesized cyclic dioxadiamides and acyclic monoxadiamides, used in ISEs. One of the cyclic
ionophores exhibited a selectivity of over 100 for lithium relative to sodium (17).
14-Crown-4 ethers have proved to be excellent ionophores for lithium ISEs, particularly when
containing bulky groups to prevent formation of the 2:1 sodium complex. Dodecylmethyl-14-crown-4
exhibits a selectivity for lithium over sodium of 150 (18), and was used to measure lithium in
undiluted serum in a flow injection analysis system containing a dialysis membrane (19). An acyclic
formazane exhibited lithium selectivity of 160:1 in an ISE (20).
A bulky dibenzo-14-crown-4 ether exhibited a preference for lithium of 800:1 in an ISE, and was
used to measure lithium in undiluted serum by placing a dialysis membrane over the electrode (21). A
di-n-butylamide 14-crown-4 ionophore exhibited a selectivity of 800:1 and could be used to measure
lithium in serum diluted 1:10 with a buffer (22).
A series of 14-crown-4 ethers with bulky groups were synthesized and tested in ISEs by Wen et al.
(23), and a selectivity of 700:1 was obtained for a tribenzo compound, double that obtained with the
dibenzo compound (21) under the same measurement conditions. The decalin 14-crown-4 ether
reported by Suzuki et al. (24) exhibited 1,000:1 selectivity for lithium, and a decalino 14-crown-4 ether
(25) topped the ISE selectivity at 2,000:1.
1. Christian, G. D. Anal. Chem. 1969
2. Gade, J. F. J. Med. J. Aust. 1949
3. Schou, M.; Juel-Nielson, N.; Stromgren, E.; Voldby, N. J. Neurol. Neurosurg. Psychiat. 1954
4. Amdisen, A. D. Handbook of Lithium Therapy
. MTP Press, Lancaster, UK, 1986.
New Engl. J. Med. 1972
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7. Trautman, J. K.; Gadzekpo, V. P. Y.; Christian, G. D. Talanta 1983
8. Attiyat, A. S.; Ibrahim, Y. A.; Christian, G. D. Microchem. J
9. Watanabe, K.; Nakagawa, E.; Yamada, H.; Hisamota, H.; Suzuki, K. Anal. Chem. 1993
10. Chapoteau, E.; Czech, B. S. P.; Zazulak, W.; Kumar, A. Clin. Chem. 1992
11. Wheeling, K.; Christian, G. D. Anal. Lett. 1984
12. Zhukov, A. F.; Erne, D.; Amman, D.; Guggi, M.; Pretsch, E.; Simon, W. Anal. Chim. Acta 1981
13. Shanzer, A.; Samuel, D.; Korenstein, R. J. Am. Chem. Soc. 1983
14. Gadzekpo, V. P. Y.; Hungerford, J. M.; Kadry, A. M.; Ibrahim, Y. A.; Christian, G. D. Anal.
15. Metzger, E.; Dohner, R.; Simon, W. Anal. Chem. 1987
16. Gadzekpo, V. P. Y.; Hungerford, J. M.; Kadry, A. M.; Ibrahim, Y. A.; Xie, R. Y.; Christian, G. D.
Anal. Chem. 1986
17. Attiyat, A. S.; Ibrahim, Y. A.; Kadry, A. M.; Xie, R. Y.; Christian, G. D. Fresenius’ Z. Anal.
18. Kitazawa, S.; Kimura, K.; Yano, H.; Shono, T. Analyst 1985
19. Xie, R. Y.; Christian, D. Anal. Chem. 1986
20. Attiyat, A. S.; Badawy, M. A.; Barsoum, B. N.; Hanna, H. R.; Ibrahim, Y. A.; Christian, G. D.
21. Kimura, K.; Oishi, H.; Miura, T.; Shono, T. Anal. Chem. 1987
22. Kataky, R.; Nicholson, P. E.; Parker, D.; Covington, A. K. Analyst 1991
23. Wen, X.; Christian, G. D.; Czech, B. P.; Bartsch, R. A. Unpublished data.
24. Suzuki, K.; Yamada, H.; Sato, K.; Watanabe, K.; Hisamoto, H.; Tobe, Y.; Kobiro, K. Anal. Chem.
25. Kobiro, K.; Tobe, Y.; Watanabe, K.; Yamada, H.; Suzuki, K. Anal. Lett. 1993
Available from the authors.
2002 by MDPI (http://www.mdpi.net). Reproduction is permitted for noncommercial purposes.
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