Metal analyses in environmental and pharmaceutical samples by capillary electrophoresis with methyl 3-amino-3-(pyridin-3-yl)propanoate dihydrochloride as a new ion-pairing reagent

Article abstract of DOI:10.1002/hlca.200590167

Separation and determination of some common metal ions was achieved with methyl 3-amino-3-( pyridin-3-yl)propanoate dihydrochloride (MAPP) as an ion-pairing reagent and pyridine as a detectable counter-ion for indirect UV detection at 254 nm. The effects of the complexing reagent and chromophore concentrations, applied voltage, and organic solvent content on the separation were investigated. The optimized separation was carried out in a running electrolyte containing 16 mM MAPP and 20 mM pyridine at pH 4.0 and was successfully applied to the qualitative and quantitative analysis of Li ⁺, Na⁺, Mg²⁺, Ca²⁺, Ba²⁺, Ni²⁺, and Zn²⁺ in pharmaceutical vitamin preparations and various water samples.

Full text of DOI:10.1002/hlca.200590167

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Helvetica Chimica Acta Vol. 88 (2005)
Metal Analyses in Environmental and Pharmaceutical Samples by Capillary
Electrophoresis with Methyl 3-Amino-3-(pyridin-3-yl)propanoate
Dihydrochloride as a New Ion-Pairing Reagent
by Gamze Kavran Belin* and Fazil Osman G¸laÁar
Laboratory of Mass Spectrometry, University of Geneva, Sciences I, Boulevard d×Yvoy 16, CH-1211 Geneva 4
(phone: ‡ 41223796394; fax: ‡ 41223793213; e-mail: Gamze.Belin@chiphy.unige.ch)
Separation and determination of some common metal ions was achieved with methyl 3-amino-3-(pyridin-3-
yl)propanoate dihydrochloride (MAPP) as an ion-pairing reagent and pyridine as a detectable counter-ion for
indirect UV detection at 254 nm. The effects of the complexing reagent and chromophore concentrations,
applied voltage, and organic solvent content on the separation were investigated. The optimized separation was
carried out in a running electrolyte containing 16 mm MAPP and 20 mm pyridine at pH4.0 and was successfully
‡
‡
applied to the qualitative and quantitative analysis of Li , Na , Mg2‡, Ca2‡, Ba2‡, Ni2‡, and Zn2‡ in
pharmaceutical vitamin preparations and various water samples.
1. Introduction. Determination of metal ions is of great interest in environmental,
medical, and pharmaceutical sample analyses. Ion chromatography (IC) is a widely
used analytical technique for metal analyses [1][2]. Capillary electrophoresis (CE) has
a number of advantages over IC, e.g., greater separation efficiency, higher selectivity,
simplicity, and adaptability to a variety of different application conditions. The
principle of separation by CE is based on differences in the mobilities of the analytes.
The difficulty of the analysis of metal ions by CE lies in that most metal ions have
roughly same mobility because of similar size and charge density. To modify the
mobilities of alkali and alkaline-earth metal ions, either complexation or ion-pairing
reagents like polyethers [3 7], carboxylic acids [8 10], 1,10-phenanthroline [11 13],
4-(2-pyridylazo)resorcinol (PAR) [14][15], 4-(2-thiazolylazo)resorcinol (TAR) [16
18], and pyridine carboxylic acids [19][20] have been used. In many cases, cationic and
neutral surfactants [21 24], organic solvents [25][26], and polyelectrolytes [27 30]
have been used in CE to improve the separation selectivity of metal ions. Because of
the transparency of inorganic cations in the UV range, UV-absorbing cationic
compounds that have similar electrophoretic mobilities, e.g., imidazole [31 33],
pyridine [34 37], aromatic amines [23][25][38][39], and Cu2‡ [40] are widely used for
the indirect detection of cations.
In this work, we investigated a new CE approach for the separation and
determination of some common metal ions by means of a new ion-pairing reagent,
methyl 3-amino-3-(pyridin-3-yl)propanoate dihydrochloride (MAPP), in the running
electrolyte, and the method was applied to the analyses of pharmaceutical vitamin
preparations and various water samples.
2. Results and Discussion. 2.1. Dependence on MAPP Concentration and pH. In
an applied electric field, all positively charged analytes are expected to migrate toward
¹ 2005 Verlag Helvetica Chimica Acta AG, Z¸rich

Helvetica Chimica Acta Vol. 88 (2005)
2323
the cathodic end according to their effective and electrophoretic mobilities (EPMs),
while MAPP would move in the opposite direction because of the carboxylate end
group. However, cationic and neutral ion-pairs formed by MAPP ions with metal ions
co-migrate in the electric field. Depending on the size and charge density of the metal
ion, the concentration of ion-pairing reagent, and the degree of ion pairing, different
metal ions exhibit different electrophoretic mobilities. The effect of MAPP on the
separation of metal ions was, therefore, investigated by increasing its concentration in
the running electrolyte containing 20 mm pyridine at pH4.0. With increasing MAPP
concentrations, the electro-osmotic mobility (EOM) decreased slightly up to 12 mm
MAPP, and, at higher MAPP concentrations, remained reasonably constant, as shown
in Fig. 1. The effect of the MAPP concentration (2.0 25.0 mm) on the effective
mobilities of the investigated metal ions is shown in Fig. 2. As expected, the effective
Fig. 1. Dependence of EOM on MAPP concentration. Electrophoresis conditions: 20 mm pyridine (pH4.0);
15 kV; injection: 8 s at 0.8 p.s.i.; indirect detection at 254 nm.
Fig. 2. Dependence of EPMs on MAPP concentration. Electrophoresis conditions: see Fig. 1.

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Helvetica Chimica Acta Vol. 88 (2005)
mobilities of cations decreased with increasing MAPP concentration, since the
mobilities of the ion pairs were smaller than those of the corresponding uncomplexed
‡
‡
forms. Complete separation of Ba2‡, Ca2‡, Na , Mg2‡, Zn2‡, Ni2‡, and Li was achieved
by the addition of 5.0 18.0 mm MAPP, with optimal separation observed at 16.0 mm.
Depending on the objectives of the application and the sample composition, different
concentrations of MAPP can be used to provide selective resolution between the
analytes. For example, in the case of Zn2‡-free samples, analysis with higher MAPP
concentrations can improve resolution, especially between Ba2‡/Ca2‡ and Na /Mg2‡
‡
ion pairs.
It is necessary for the pHto be acidic for sufficient protonation of the visualization
reagent, and Timerbaev [25] reported an upper pHlimit of ca. 5 to prevent metal
hydrolysis. For this reason, the effect of pHon the separation was investigated in a
running electrolyte containing 16 mm MAPP, and pH4.0 was found to be the best
working pH(not shown). At lower pHvalues,
e.g., 3.0, EOM decreased but
deterioration of the resolution of some peaks, due to peak tailing, was observed. At
pH5.0, the EOM increased slightly and resolutions decreased.
2.2. Dependence on Pyridine Concentration. The effect of the concentration of
pyridine used as the visualizing agent for the indirect detection of metal ions on the
separation is shown in Fig. 3. 20 mm was chosen as optimal pyridine concentration. The
separation between Mg2‡/Zn2‡ and Zn2‡/Ni2‡ ion pairs could not be achieved at lower
concentrations of pyridine. No improvements were observed at 25 mm, especially in
terms of the effective mobilities of the metal ions, but the increased viscosity of the
running electrolyte led to a decrease in peak sharpness and an increase in the analysis
time.
Fig. 3. EPMs as a function of pyridine concentration. Electrophoresis conditions: 16 mm MAPP (pH4.0);
15 kV; injection: 8 s at 0.8 p.s.i.; indirect detection at 254 nm.
2.3. Dependence on Voltage. Separation voltages ranging from 10 to 30 kV were
applied from the anodic side, and the effective mobilities of metal ions were
investigated to find optimal voltage conditions (Fig. 4). The mobilities of all metal ions
‡
except Li increased slightly from 10 to 15 kV, then remained effectively constant up to
30 kV. The effect of voltage (10 30 kV) on the resolution (Rs) of investigated metal

Helvetica Chimica Acta Vol. 88 (2005)
2325
ions is shown in Table 1. Rs Values were calculated as 2(t2 À t1)/(w1 ‡ w2), where t1 and
t2 are the migration times and w1 and w2 are the peak widths of the analytes. For the
‡
choice of the optimal voltage, the resolution of the Ni2‡/Li pair can be omitted since it
has the largest value at all voltages. Thus, the best voltage for the overall separation of
the remaining metal ion pairs, i.e., 15 kV, was selected as the working voltage.
Fig. 4. Dependence of EPMs on voltage. Electrophoresis conditions:16 mm MAPP ‡ 20 mm pyridine (pH4.0);
injection: 8 s at 0.8 p.s.i.; indirect detection at 254 nm.
Table 1. Dependence of Resolution (Rs) of Metal Ion Pairs on Voltage (V [kV])
a
V [kV]
Rs
)
‡
‡
‡
Ba2‡/Ca2‡
Ca2‡/Na
Na /Mg2‡
Mg2‡/Zn2‡
Zn2‡/Ni2‡
Ni2‡/Li
10
15
20
25
30
1.82
1.92
1.92
1.76
2.20
1.87
2.01
1.84
1.63
2.01
2.06
1.96
1.90
1.75
1.84
0.84
0.87
0.75
0.84
0.72
1.25
1.69
1.06
1.38
1.05
5.44
4.98
5.02
6.04
5.65
a) Rs calculated as 2(t2 À t1)/(w1 ‡ w2), where t is migration time and w is peak width.
2.4. The Presence of an Organic Modifier. MeOH, MeCN, and acetone over a
concentration range of 0 20% (v/v) were investigated as organic modifiers. The
effects of each solvent on the separation are shown in Fig. 5. The EOM decreases
sharply (from 3.27 Â 10À4 to 2.47 Â 10À4, 3.17 Â 10À4, and 2.41 Â 10À4 cm2 VÀ1 sÀ1 for
MeOH, MeCN, and acetone, respectively) when 5% (v/v) of organic solvent is added to
the running electrolyte and continues to decrease slightly (down to 2.03 Â 10À4, 2.64 Â
10À4, 2.01 Â 10À4 cm2 VÀ1 sÀ1 for MeOH, MeCN, and acetone, respectively) by
increasing the modifier concentration up to 20% (v/v), as expected, considering the
increased viscosity of the electrolyte solution. Electrophoretic mobilities of metal ions
and the resolution of peaks, especially between Mg2‡/Zn2‡ and Zn2‡/Ni2‡ pairs, were
decreased by the addition of organic solvent. The use of an organic modifier is,
therefore, not recommended.

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Helvetica Chimica Acta Vol. 88 (2005)
Fig. 5. Effect of addition of a) MeOH, b) MeCN, or c) acetone on the separation
3. Quantification. The separation of seven metal ions under optimized conditions,
i.e., 16 mm MAPP, 20 mm pyridine (pH4.0), and 15 kV, is shown in Fig. 6. The limits of
detection (LODs), relative standard deviations (RSDs (%)), and regression lines are

Helvetica Chimica Acta Vol. 88 (2005)
2327
‡
‡
Fig. 6. Electropherogram of metal ions (Mg2‡, Ba2‡, Ca2‡, Na , Zn2‡, Ni2‡, and Li ). Running electrolyte:
16 mm MAPP ‡ 20 mm pyridine (pH4.0); 15 kV; injection: 8 s at 0.8 p.s.i.; indirect detection at 254 nm; [Mg 2‡
in the sample ˆ 0.3 mm; remaining ions at 0.4 mm.
]
Table 2. Analytical Characteristics of the Method
Metal ion
LOD [mg/l]a)
RSD%b)
Regression-line parametersc)
R2 d
)
t [min]
Peak area [AU]
Ba2‡
Ca2‡
Na
11.5
2.28
1.05
0.77
9.81
6.45
0.62
0.83
0.87
0.93
0.96
0.95
0.98
1.18
3.43
0.85
2.12
4.93
4.58
1.35
4.98
y ˆ 0.07  103 x À 4.82  102
y ˆ 0.30  103 x ‡ 2.70  102
y ˆ 0.58  103 x À 0.65  102
y ˆ 0.50  103 x À 1.95  102
y ˆ 0.10  103 x À 3.85  102
y ˆ 0.18  103 x À 4.16  102
y ˆ 1.35  103 x À 1.63  102
0.9985
0.9997
0.9983
0.9997
0.9983
0.9989
0.9997
‡
Mg2‡
Zn2‡
Ni2‡
‡
Li
a) Limits of detection; signal/noise ˆ 3. b) Relative standard deviation (RSD%); n ˆ 10. c) y ˆ corrected peak
area [AU], x ˆ conc. [mg/l]. d) Correlation coefficient.

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Helvetica Chimica Acta Vol. 88 (2005)
reported in Table 2. In the equations of calibration graphs, y is the corrected peak area
(arbitrary units), x is the concentration in mg/l, and R2 is the correlation coefficient.
The method was applied to the analysis of pharmaceutical vitamin-mineral tablets and
water samples to evaluate the qualitative and the quantitative performance. Table 3
gives the quantitative results obtained with five replicates of each sample. Recoveries
of metal ions were estimated by adding a known amount of each metal ion into the
sample. Vitamin tablet 1 was diluted 1:50 (v/v) for Zn2‡ and 1:400 (v/v) for Ca2‡ and
Mg2‡ analyses since the Zn2‡ content was lower than the LOD under the higher dilution
conditions used for Ca2‡ and Mg2‡ (Fig. 7). Fig. 8 shows the analysis of interstitial water
of a lacustrine surface sediment. The electropherograms of all samples gave migration
times for the metal ions identical to those in Fig. 7.
Table 3. Quantitative Sample Analysis Results
Sample
Metal
ion
Dilution
factor
Quantity
[mg/l]a)
Listed
Added
amount
[mg/l]c)
Total
Recovery
[%]
amount
amount
[mg/l]b)
[mg/l]a)
Vitamin tablets
1
Ca2‡
Mg2‡
Zn2‡
Ca2‡
1 : 400
1 : 400
1 : 50
21.6 Æ 0.7
9.5 Æ 0.3
14.5 Æ 0.4
6.3 Æ 0.5
1.94 Æ 0.03
2.5 Æ 0.2
9.4 Æ 0.2
10.9 Æ 0.4
20.0
10.0
15.0
5.13
n.l.
2.12
10.0
n.l.
10
10
10
10
10
10
10
10
31.2 Æ 0.5
19.4 Æ 0.4
23.9 Æ 0.6
16.4 Æ 0.3
12.6 Æ 0.5
12.4 Æ 0.3
19.7 Æ 0.4
20.8 Æ 0.5
98.7
99.4
97.6
100.6
105.5
99.7
101.7
99.5
2
3
1 : 400
‡
Na
Mg2‡
Ca2‡
1 : 4000
‡
Na
Tap-water samples
1
Ca2‡
Na
Mg2‡
Ca2‡
1 : 1
1 : 1
20.6 Æ 0.3
4. 9 Æ 0.3
3.8 Æ 0.2
10
10
10
10
10
10
30.8 Æ 0.3
14.8 Æ 0.2
13.6 Æ 0.2
32.2 Æ 0.5
19.6 Æ 0.2
13.5 Æ 0.5
100.6
99.4
98.2
99.3
97.5
98.4
‡
2
22.4 Æ 0.4
10.1 Æ 0.2
3.72 Æ 0.08
‡
Na
Mg2‡
Ca2‡
Sedimentd)
1 : 1
52.4 Æ 0.5
3.6 Æ 0.2
10.2 Æ 0.2
10
10
10
62 Æ 1
99.6
100.3
97.5
‡
Na
13.6 Æ 0.2
19.7 Æ 0.3
Mg2‡
a) The results are based on analysis of five replicates. b) Declared by the manufacturer; n.l. ˆ not listed.
c) Added to samples to facilitate estimation of metal ion recovery. d) Supernatent interstitial water from a
centrifuged lacustrine surface sediment sample.
4. Conclusions. A simple and effective CE method for the analysis of metal ions
based on the use of a new ion-pairing reagent, MAPP, has been developed. Pyridine
was used for indirect UV detection of metal ions. Complete separation of the
investigated metal ions could be performed in less than 4 min with good reproducibility
and high peak symmetry. The potential of the proposed method was demonstrated by
its application to the analysis, without any tedious sample preparation, of metal ions
commonly found in environmental water and pharmaceutical vitamin samples. The

Helvetica Chimica Acta Vol. 88 (2005)
2329
Fig. 7. Electropherogram for vitamin tablet 1. Electrophoresis conditions: see Fig. 6.
results obtained from the vitamin analyses are in good agreement with the contents
cited by the manufacturers.
Experimental Part
‡
‡
1. General. All chemicals were purchased from Fluka (Buchs, Switzerland). Solns. of alkali (Li , Na ),
alkaline-earth (Mg2‡, Ca2‡, Ba2‡), and transition (Zn2‡, Ni2‡) metal ions were prepared from reagent-grade
chloride or bromide salts. Vitamin-mineral preparations were obtained from local pharmacies in Switzerland
and Turkey. Electrophoresis was performed on a Beckman P/ACE MDQ system (Fullerton, CA, USA)
equipped with a photodiode-array UV detector from Beckman Technologies with detection at 254 nm. The
system was controlled with 32 KaratTM software; an uncoated fused silica capillary of 50 mm I.D. Â 375 mm O.D.,
with total and effective lengths of 57 and 50 cm, resp. (Agilent, Switzerland) was used at 258. 1H- and 13C-NMR
Spectra: Bruker DRX-500 Larmor-frequency spectrometer; in D2O, d in ppm. MS: Finnigan MAT SSQ-7000
mass spectrometer with an ESI interface: in m/z.
2. Sample Preparation. Stock solns. of each cation (10 mm) were prepared and diluted to the specified
concentrations with deionized water before analysis. Vitamin-mineral tablets were dissolved in 25 ml deionized
water and diluted to appropriate concentrations for CE analyses. Surface sediment samples from Motte Lake
(France) were centrifuged at 6000 r.p.m. for 6 min before analysis of the supernatant.
3. Methyl 3-Amino-3-(3-pyridinyl)propanoate Dihydrochloride (MAPP, 5). MAPP was synthesized as
summarized in the Scheme. Nicotinic acid ( ˆ pyridine-3-carboxylic acid, 1; 15 g, 0.12 mol) was dissolved in
concentrated H2SO4 (0.33 mol) and refluxed with MeOH(100 ml) for 2 h to give the methyl ester 2 [41]; 2
(0.1 mol) was then converted to the b-keto ester 3 with sodium methoxide (0.15 mol) [42], and then NH3 gas
(0.24 mol) was bubbled through the soln. to give the enamine 4 [43]. Compound 4 was reduced by reaction with
NaBH4 (0.2 mol) in AcOH(1.56 mol) and THF (100 ml) [43] to give 9.35 g of the desired product 5 (43% yield).
1H-NMR (500 MHz, D2O): 3.34 (dd, 1 H); 3.39 (dd, 1 H); 3.74 (s, 3 H); 5.21 (t, 1 H); 8.22 (m, 1 H); 8.81 (m,

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Helvetica Chimica Acta Vol. 88 (2005)
Fig. 8. Electropherogram obtained for a sample of interstitial water from a lacustrine surface sediment.
Electrophoresis conditions: see Fig. 6.
1 H); 8.94 (m, 1 H); 9.05 (s, 1 H ).13C-NMR/DEPT (125 MHz, D2O): 171.1 (CˆO); 145.5 (CH); 142.9 (CH);
‡
141.5 (CH); 135.5 (C); 128.1 (CH); 52.9 (CHNH 2); 48.5 (MeO); 36.8 (CH2). ESI-MS: 181 (MH , free base).
4. Electrophoresis. A new fused-silica capillary was rinsed with MeOH, 1m HCl, 1m NaOH, 0.1m NaOH,
deinonized water, and running electrolyte for 5, 5, 30, 10, 5, and 10 min, resp. Between injections, the capillary
was rinsed with running electrolyte for 2 min. pHValues were adjusted with 0.1m HCl. Hydrodynamic injection
was performed at 0.8 p.s.i (1 p.s.i ˆ 6894.76 Pa) for 8 s, and the applied voltage was set at 15 kV at the anode.

Helvetica Chimica Acta Vol. 88 (2005)
Scheme. Synthesis of MAPP
2331
a) H2SO4, MeOH, 658. b) NaOMe, MeCOOEt. c) Toluene, i-PrOH, HCOOH, 658, NH3. d) NaBH4, AcOH,
THF, HCl, À 58.
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Received February 28, 2005