Novel flow-through bulk optode for spectrophotometric determination of lithium in pharmaceuticals and saliva

Sensors and Actuators B 145 (2010) 133–138

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Novel flow-through bulk optode for spectrophotometric determination of lithium in pharmaceuticals and saliva ˜ M.S. García ∗ , M. Cuartero, M.C. Alcaraz M.I. Albero, J.A. Ortuno, Department of Analytical Chemistry, Faculty of Chemistry, University of Murcia, 30071 Murcia, Spain

a r t i c l e

i n f o

Article history: Received 28 July 2009 Received in revised form 12 November 2009 Accepted 20 November 2009 Available online 3 December 2009 Keywords: Flow-through optode Sensor Lithium Pharmaceuticals Human saliva

a b s t r a c t A new flow-through spectrophotometric bulk optode for the determination of lithium is reported. The optode membrane incorporates a lipophilic pH indicator (chromoionophore XIV), a lipophilic neutral ionophore (lithium ionophore VIII) and potassium tetrakis[3,5-bis(trifluoromethyl) phenyl] borate (ionic additive) as active constituents in a plasticized poly(vinyl) chloride membrane, entrapped in a cellulosic support. The composition of the membrane was tested using two different plasticizers. The optode was incorporated in a flow-injection system optimized for the determination of lithium. The analytical performance of the optode was evaluated, obtaining a linear concentration range of two decades of concentration (1 × 10−4 to 1 × 10−2 M), a limit of detection of 1.4 × 10−4 M, a fast sample throughput (25–4 samples h−1 ) and good reproducibility and selectivity. The sensor was seen to exhibit a fully reversible response. The proposed FI method is applied to the determination of lithium in pharmaceuticals and human saliva with satisfactory results. © 2009 Elsevier B.V. All rights reserved.

1. Introduction Lithium ion sensors are currently in demand for their potential biomedical applications. The therapeutic effects of lithium salts have proved useful in the treatment of manic depressive, hyperthyroidism and certain types of cancer, and have also been proposed for help in the prevention of Alzheimer’s disease [1]. Lithium salts, normally administered as lithium carbonate, have widely been employed in the control of bipolar disorder symptoms [2] and have been seen to be efficient at plasmatic concentrations higher than 0.50 mmol l−1 . However, some cases of severe intoxication at lithium concentrations above 1.5 mmol l−1 , and even death at concentrations 2–2.5 mmol l−1 , are related in the literature [3,4], emphasising the narrow therapeutic window available. Therefore, the monitoring of lithium levels in drugs and biological fluids is important to ensure adequate and safe treatment. A review of the literature revealed that several analytical methods have been described for lithium monitoring in different kinds of sample, including spectrophotometry [5,6], flame photometry [7], fluorimetry [8], chromatography [9,10], potentiometry [11,12] and atomic absorption and emission [13,14].

∗ Corresponding author. Tel.: +34 868 887404; fax: +34 868 887682. E-mail address: [email protected] (M.S. García). 0925-4005/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.snb.2009.11.053

The use of optical sensors is considered a simple, quick and inexpensive method of analysis. The development of optical chemical sensors (optodes) as viable alternative to other types of sensor is of great interest [15] and several optodes have been applied in the trace analysis of heavy metals in control processes and environmental and medical analyses [16]. One type of optode makes use of a plasticized polymeric membrane and is based on the reversible mass transfer of analyte from the sample into the bulk of the sensing layer. This type of optical sensor was named “bulk optode membrane” by Seiler and Simon, who described the basic principles and techniques that can be used with it [17]. Several ionophores and appropriate lipophilic pH indicator dyes introduced into the membranes have been used to design optical cation-sensing systems [18]. Optical transduction is based on the protonation and deprotonation of the pH indicator dye related with the cation concentration present in the membrane. The performance of reversible bulk optodes is probably best tested in flow-injection systems (FI), a configuration that provides greater flexibility and the possibility of automation, in addition to a wider applicability to real samples. Some optodes for lithium determination have been proposed in the literature [19–25]. The goal of this work was to develop and optimize a flowthrough bulk optode for the FI-spectrophotometric determination of lithium in pharmaceuticals and human saliva. The originality of the present paper with respect to previous lithium optodes was to exploit the analytical possibilities in flow-injection systems and to cope with the analysis of saliva samples.

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2. Experimental 2.1. Reagents and materials All chemicals were of analytical reagent grade and Milli-Q water was used throughout. Polyvinyl chloride (PVC) of high molecular weight, 2-nitrophenyl octyl ether (NPOE), bis(2-ethylhexyl) sebacate (DOS), 2-[2-9-acridinyil)vinyl]-5-(diethylamino)phenyl stearate (chromoionophore XIV), potassium tetrakis[3,5-bis (trifluromethyl)phenyl]borate, N,N,N ,N ,N ,N -hexacyclohexyl4,4 ,4 -propylidynetris(3-oxabutyramide) (lithium ionophore VIII) and tetrahydrofuran (THF) were obtained from Fluka. Filter paper 235 from Albet. Lithium chloride solution (8 M solution) from Sigma. A 0.02 M buffer solution of pH 4.5 was prepared by mixing appropriate amounts of MgAc2 and HAc solutions. Lithium working solutions within the concentration range 1.0 × 10−4 M to 1.0 × 10−2 M were prepared by serial dilutions of the 8 M lithium chloride solution with the Ac− /HAc buffer of pH 4.5. Pharmaceutical: Plenur tablets (FAES FARMA, Vizcaya, Spain) containing 400 mg of lithium carbonate and excipients. 2.2. Apparatus All spectroscopic measurements were made using a Metrohm LTD CH-9100 (Herisau, Switzerland) photometer equipped with light-guide cell for direct measurements, available wavelength range 400–700 nm and with an analogue-to-digital converter. The FI system (Fig. 1(a)) consisted of a carrier solution (2.0 × 10−2 M Ac− /HAc buffer of pH 4.5) propelled by a peristaltic pump through polytetrafluoroethylene (PTFE) tubing (0.5 mm i.d.) at a flow rate of 0.8 ml min−1 . The sample injections (230 ␮l) were made by an Omnifit injection valve fitted with a sample loop. A home-made flow-through cell (Fig. 1(b)) designed by the authors and described previously [26] was used in the FI system. The body consists of two separate Perspex blocks (length 5.5 cm, width 1.7 cm and height 1.5 cm) tightly pressed together by screws. The upper block was drilled (1.3 cm) to fit the optical fiber, and a glass window was sealed in the lower part of this hole with epoxide cement. The upper block was also drilled to accommodate the inlet and outlet PTFE tubes. A mirror was placed on to the lower block to avoid any loss

of light. A gasket of parafilm paper was placed on the mirror and the membrane optode was then pressed firmly on to the gasket. Finally, a thick gasket made of parafilm paper folded to obtain twelve layers, through which a hole was made, was placed between the two blocks. The solution cavity was defined by the front window of the cell, the thick gasket and the optode membrane. 2.3. Optode membrane preparation The optode membrane was prepared by dissolving 50 mg of PVC, 100 mg of DOS, 1.6 mg of chromoionophore XIV, 2.8 mg of lithium ionophore VIII and 2.2 mg of ionic additive in 3.0 ml of THF. Then, 50 ␮l of this mixture was deposited on a cellulose filter paper. After a few minutes, the THF had evaporated giving rise to a plasticized PVC membrane, containing the dissolved reagents, entrapped into the cellulose paper. A piece (2.0 cm × 3.0 cm) was cut out and incorporated into the flow-through cell, which was then incorporated into the FI system selected. 2.4. Procedures 2.4.1. Calibration of the sensor Spectroscopic measurements were carried out in the flowinjection mode. Aliquots (230 ␮l) of lithium working solutions (1.0 × 10−4 to 1.0 × 10−2 M) were injected in the FI system to obtain a calibration graph by monitoring the peaks of the different working solutions. The corresponding peaks height values obtained were plotted against the corresponding concentrations and were fitting to a linear regression. 2.4.2. Determination of lithium in pharmaceutical The lithium content in tablets was determined by analysing three tablets separately, each one powdered and dissolved with 10 ml of water. The mixture was then introduced into an ultrasonic bath for 30 min, filtered through a filter paper and the filtrate was diluted with Ac− /HAc buffer of pH 4.5 in a 200-ml calibrated flask. Adequate aliquots of this solution were diluted with Ac− /HAc buffer of pH 4.5. The lithium concentration was obtained following the recommended procedure described above, making the measurements in triplicate and obtaining the corresponding concentration from the calibration graph. 2.4.3. Determination of lithium in saliva In the absence of saliva samples containing lithium, known amounts of lithium were added to different saliva samples obtained from untreated volunteers. About 5 ml of saliva sample was centrifuged at 3000 rpm for 15 min and aliquots of 1.0 ml of the supernatant were diluted with 1.0 ml of Ac− /HAc buffer of pH 4.5. The lithium concentration was determined following the recommended procedure described above. A saliva blank (saliva without any lithium added) was also run to correct the values. 3. Results and discussion 3.1. Principle of operation

Fig. 1. (a) Flow-injection system. A, carrier Ac− /HAc buffer solution pH 4.5; B, peristaltic pump (0.8 ml min−1 ); C, sample injection valve (230 ␮l); D, flow-through cell; E, optical fiber; F, spectrophotometric detector; G, analogue-to-digital converter; H, personal computer; W, waste. (b) Schematic representation of the flow-through cell.

The proposed flow-through optode membrane was prepared by incorporation of an ionophore (L) which selectively forms complex with Li+ acting such as neutral ligand, and a chromoionophore (Ind) that interacts with the reference ion (H+ ) and changes optical properties upon protonation (the indicator is green in its acidic form and yellow in its basic form). The third component involved in the mechanism response is a lipophilic cation-exchanger (R). Because the concentration of cation-exchanger in the matrix is limited, the competition between the two ions for the cation-exchanger sites affects the fraction of protonated chromoionophore (IndH+ ) and

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135

Fig. 2. Response mechanism of the optode.

determines the sensor response. Since the pH in the aqueous sample is buffered, the optode responds to the metal activity in the sample. Taking all this into account, the response mechanism of the proposed optical system can be explained by the scheme shown in Fig. 2. 3.2. Study of variables 3.2.1. Membrane composition The proposed sensor consisted of a plasticized PVC membrane, in whose bulk the reagents are dissolved, entrapped in the porous cellulosic support thus providing a high contact surface for the contact with the sample solution. This type of membranes provided a fast response toward different ions that served as the base for the development of the corresponding optical sensors [26,27]. It is well known that the membrane composition can substantially affect the response characteristics and working concentration range of the optical sensor [12]. Thus, the effects of the nature of plasticizer and the presence or absence of the additive on the response behaviour of the membrane sensor were investigated. The compositions of the three membranes assayed are shown in Table 1. In these membranes the amounts of PVC, plasticizer, chromoionophore and ionophore were kept constant. The nature of the plasticizer affects the dynamic concentration range and selectivity behaviour of the sensing membrane. The calibration slopes and the limits of detection of the membranes constructed using two different plasticizers (DOS and NPOE), shown in Table 1, revealed that the membrane including DOS had the most sensitive response to lithium. The membrane prepared with DOS and without the ionic additive (membrane C) showed no response up to a lithium concentration as high as 1 M. Taking into account these results, membrane A (31.9% PVC, 63.9% DOS, 1% Ind, 1.8% L and 1.4% R was selected for further studies. 3.2.2. Spectral characteristics Diffuse reflectance spectra of the optode membrane are shown in Fig. 3. Spectra corresponding to the protonated and deprotonated form of pH indicator were obtained by pumping 2.0 × 10−1 M HAc or 1.0 × 10−2 M NaOH solutions, respectively. The spectra are given as relative reflectance R/Rb , where R is the diffuse reflectance of the selected membrane and Rb is the diffuse reflectance of a membrane containing only with PVC and DOS. The greatest difference in the reflectance ratio between the protonated and deprotonated forms was found at 620 nm,

Fig. 3. Diffuse reflectance spectra of the selected membrane in the deprotonated (curve 1) and protonated forms (curve 2).

so this wavelength was selected for all subsequent reflectance measurements. 3.2.3. Optimization of the FI system The influence of the FI variables, sample volume and flow rate, was studied by injecting a 5.0 × 10−3 M solution of lithium at different values of these variables. The length of the tubing from injection valve to FIA-cell was the minimum distance possible (40 cm) in order to minimize dispersion. Fig. 4(a) shows the influence of sample volume on the peak height (curve 1) and on the peak width (curve 2). As can be seen, increasing sample volumes increased the peak height but the peak width increased dramatically above a sample volume of 230 ␮l, which involved a corresponding decrease in the sampling frequency. Taking this into account, a sample volume of 230 ␮l was chosen for further studies. The effect of flow rate is shown in Fig. 4(b), where it can be seen that both peak height and width decreased as the flow rate was increased. As a compromise between sensitivity and sampling frequency, a flow rate of 0.8 ml min−1 was selected. 3.2.4. Effect of the pH Other authors demonstrated that pH indicator here selected can be used to make optode membrane with excellent operating characteristics and that the sensitivity can be tuned by variation of sample pH [28]. The effect of the pH on the response of the proposed bulk optode was studied by pumping as carrier Ac− /HAc buffer solutions of pH values of 3.6, 4.5 and 5.0, and injecting sample solutions of lithium 5.0 × 10−3 M prepared in the same carrier medium. The peak heights obtained in reflectance arbitrary units

Table 1 Composition of the membranes assayed. Membrane

A B C a

Reflectance (u.a.)/M.

Percentage (w/w) of components in membranes NPOE

PVC

DOS

Ind

L

R

– 64 –

32 32 31

64

1.0 1.0 1.2

1.8 1.8 1.8

1.2 1.2 –

66

Slopea

LOD (M)

877.0 251.3 –

1.4 × 10−4 1.2 × 10−2 –

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Fig. 4. Effect of sample volume (a) and flow rate (b) on the analytical signal (curves 1) and on the peak width at 90% (W0.9 ) (curves 2).

(u.a.) were 1.0, 4.9 and 3.2, respectively. The highest response was obtained at pH 4.5 so this value was selected for further studies. 3.3. Performance characteristics The dynamic reflectance response and the corresponding calibration graph, obtained under the selected experimental conditions, for lithium concentrations in the range 1 × 10−4 to 1 × 10−2 M are shown in Fig. 5. The peaks height obtained were fitted to a linear regression and the regression equation obtained was: Peak

height (reflectance/a.u.) = 0.378 + 877.0 [Li+ ] (M); with a correlation coefficient of 0.9998. The detection limit, calculated as the concentration of Li+ which provided a signal equal to three times the noise [29] was estimated to be 1.4 × 10−4 M. The repeatability of the peak height was studied by performing 10 consecutive injections of a 5 × 10−3 M Li+ working solution. The variation coefficient of peak height for was ±1.1%. The reproducibility of the peak height between days was obtained from the injections of a 5 × 10−3 M Li+ working solution made in four days chosen arbitrarily over a period of 40 days. In any of these days the injections were made by triplicate and the mean value was used. A variation coefficient value of ±4.1% was obtained. The reproducibility of the response between different membranes was obtained from the response of four membranes. For each membrane the mean peak height values corresponding to the injection of a 5 × 10−3 M Li+ working solution made by triplicate was obtained. The variation coefficient between the mean values obtained was ±5.1%. The optode worked well for at least 1 month under moderate use, during which time no appreciable change in the calibration characteristics was observed. The sample throughput depends on the Li+ concentration to be determined, reaching values between 25 and 4 samples h−1 for a concentration range of 1 × 10−4 to 1 × 10−2 M. 3.4. Sensor selectivity The selectivity of the optode was tested for several cations (Na+ , K+ , Ca2+ and Mg2+ ) that are normally present in biological fluids. The selectivity coefficients of these cations were determined by applying the separate solution method [30], comparing the concentrations that generate the same peak height for the primary and interfering ion, applying Eq. (1). KLi,J =

Fig. 5. Dynamic response and corresponding calibration graph; 1: 1 × 10−4 M, 2: 5 × 10−4 M, 3: 1 × 10−3 M, 4: 2 × 10−3 M, 5: 5 × 10−3 M, 6: 1 × 10−2 M.

C

 Li1/zJ CJ

(1)

The calibration graph was used to calculate the concentration of Li+ that corresponds to the peak height observed for the concentration of interfering ion assayed. As can be seen, the values obtained for the selectivity coefficient (Table 2) are relatively low.

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Although Li+ can be determined by blood analysis, it is preferable to determine the Li+ concentration in saliva because it is more easily extracted. The effective therapeutic lithium range in saliva is 1.5–2.5 mM, twice that in the blood [31]. For the determination of lithium in human saliva possible interference from the sample matrix was tested by making calibration graphs with three saliva samples and the calibration parameters obtained were compared with the general calibration graph. No significant differences were found between them and therefore there was no matrix effect. Lithium concentration in saliva samples was determined as described in Section 2. In the absence human saliva samples containing lithium, known amounts of Li+ were added to blank samples; the results obtained are summarized in Table 4. Good recoveries were obtained in almost all cases. In the case of the pharmaceutical and the salive 4, the lithium content was also determined by ICP. The results obtained were compared with those obtained by our method applying the t test and the F test at the 95% confidence level. No significant differences in accuracy and precision were found between the two methods.

Table 2 Selectivity coefficients of the species assayed. Species (J) +

Na K+ Rb+ Cs+ Ca2+ Mg2+ Sr2+ Ba2+

Concentration assayed (M)

KLi,J

0.2 2 3 2 0.02 3 0.02 0.01

9.6 × 10−3 5.1 × 10−4 2.1 × 10−4 3.8 × 10−4 4.1 × 10−2 1.6 × 10−3 3.5 × 10−2 1.0 × 10−1

137

3.5. Analytical applications The proposed FI method was used to determine lithium in pharmaceuticals and in human saliva. In pharmaceutical analysis it is important to test the selectivity toward excipients and fillers added to the preparations. The possible interferences were studied by adding different amounts of the possible interferent to samples containing 10−2 M Li+ and applying the proposed method. No interference was observed in the presence of magnesium stearate, magnesium carbonate, polyethylene glycol, talcum, titanium dioxide, carboxipolymethylene, tilose or polymetacrylate even at amounts higher than those contained in the preparations in study. The lithium content in tablets dosage was determined as described in Section 2. Good recoveries were obtained in all cases as can be seen in Table 3.

3.6. Comparison with other optodes for lithium determination A survey in the literature on the optodes for the determination of lithium reveals that most papers come from the group of Suzuki, which has been providing valuable papers on this subject since

Table 3 Determination of lithium in pharmaceuticals. Sample

Labelleda

Reported methoda

Proposed methoda

Addeda

Founda

Recovery (%)b

Plenur

37.6

36.9 ± 0.6b

37.5 ± 0.6b

7.4 17.4 22.3 29.8

7.3 17.5 22.7 29.6

99.7 100.7 102.0 99.2

a b

± ± ± ±

2.1 2.5 1.7 3.5

mg Li+ /tablet. Mean ± SD (n = 3).

Table 4 Determination of lithium in spiked saliva samples. Added (␮g/ml)

Found (␮g/ml)

Recovery (%) ± SDa

1

1.74 3.47 10.41

2.00 3.62 10.16

115.2 ± 0.0 96.8 ± 2.5 97.6 ± 2.9

2

1.74 3.47 10.41

1.75 3.75 10.16

100.8 ± 4.9 108.3 ± 2.7 97.63 ± 2.9

3

1.74 3.47 10.41

2.00 3.50 10.16

105.2 ± 0.1 101.0 ± 0.2 97.6 ± 2.9

4

6.94 6.94

Saliva sample

a b

96.3 ± 2.8 97.4 ± 3.1

6.68 6.76b

Mean ± SD (n = 3). ICP determination.

Table 5 Comparison with other optodes for the determination of lithium. Reference

Analytical signal

[21]

Fluorescence

[22] [23] [24] [25] Proposed method

Digital-color Fluorescence Digital-color Absorbance Reflectance

LD (M) −3

1 × 10 1 × 10−4 1 × 10−6 4 × 10−4 1 × 10−5 1 × 10−5 1 × 10−4

Linear range (M) −3

1 × 10 1 × 10−4 1 × 10−6 3 × 10−2 1 × 10−5 1 × 10−3 1 × 10−4

−1

to 1 × 10 to 1 × 10−1 to 1 to 4.4 × 10−1 to 1 × 10−1 to 1 × 10−1 to 1 × 10−2

Sample throughput (simples h−1 )

KLi/Na

2–6 – – 2–10 – 3 4–25

−2.4 −3 – No interfere up to 10−2 M −4 −2.0

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1993. They have used absorbance [25], fluorescence [21,23] and digital-color analysis [22,24]. A comparison among the different optodes including the proposed here (Table 5), shows that the lower concentration of Li+ determined is reached by the digital-color analysis using mixed dyes [22]. The lowest selectivity coefficient Li/Na was obtained with a 14-crown-4 derivative (PTM14C4) as ionophore [25]. It seems that the highest sample throughput is achieved with our method. While a sigmoidal dependence between signal and the logarithmic concentration is obtained in other papers, a linear relationship between the signal and concentration is used here. The sigmoidal response obtained for other lithium optodes corresponds to the steady-state reflectance for equilibrium, while in our flow-injection method the reflectance in the peak has not reached that value. In our method, kinetic factors, both physical and chemical, influence the dependence between the analytical signal and the concentration giving rise to a linear response within a certain concentration range. With regard to the applications of the lithium optodes, it seems that the final aim of this research is the determination of lithium in human serum and saliva. Although the group of Suzuki gave some steps in this direction, we think that our paper is a further step in achieving this goal. 4. Conclusion The optode membrane proposed for the spectrophotometric determination of lithium is easily prepared and incorporated in a flow-injection system using a flow-through cell and provides a simple, rapid and inexpensive method. The optode is applicable for the determination of lithium in pharmaceuticals and in saliva within the therapeutical range.

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Biographies M.I. Albero obtained her PhD in 1972 (University of Murcia UM, Spain) in Chemical Sciences. She is a Professor Titular in the Department of Analytical Chemistry at the University of Murcia. She is a member of the Automatic Methods of Analysis and Sensors Group at UM. Her current research interests are on chemical sensors and flow analysis. ˜ obtained his PhD in 1983 (University of Murcia UM, Spain) in Chemical J.A. Ortuno Sciences. He is currently a Catedratico in the Department of Analytical Chemistry at the University of Murcia. He is Director of the Automatic Methods of Analysis and Sensors Group in UM. His current research interests are on development and applications of optical sensors, ion-selective electrodes and amperometric sensors based on ITIES (Interface between Two Immiscible Electrolyte Solutions). M.S. García obtained her PhD in 1975 (University of Murcia UM, Spain) in Chemical Sciences. She is currently a Professor Titular in the Department of Analytical Chemistry at the University of Murcia. She is a member of the Automatic Methods of Analysis and Sensors Group at UM. Her current research interests are on chemical sensors and flow analysis. M. Cuartero received his MSc in Chemistry in 2009 from the University of Murcia. ˜ She is pursuing a PhD in Chemistry under the supervision of Dr. J.A. Ortuno. M. C. Alcaraz is completing her Barchelor thesis based on optical sensors.