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Differential Pulse Polarographic Determination of some Barbiturates.

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319186
Polarographic Determination of Barbiturates
149
Arch. Pharm. (Weinheim) 319, 149-154 (1986)
Differential Pulse Polarographic Determination of some
Barbiturates')
Aytekin Temizer* and Ali Osman Solak
Department of Analytica1 Chemistry, Faculty of Pharmacy, Hacettepe University, Ankara,
Turkey
Eingegangen am 11. Dezember 1984
A differential pulse polarographic method for the determination of some barbiturates is described.
The analysis is achieved in 0.05 M borate buffer at pH = 9.30 and based on the formation of insoluble
mercury salts of barbiturates. The relationship between the barbiturate concentration and the peak
current is linear over the concentration range of 4-100 pM. Preliminary treatment is not required and
the method is simple, specific and applicable to the assay of composite tablets. The nature of the
electrode process and the mechanism were elucidated.
Dinerentieiie Pulspolarographische Bestimmung einiger Barbiturate
Es wird eine differentieile Pulspolarographische Methode zur Bestimmung einiger Barbiturate
beschrieben. Die Analyse wird in einem Boratpuffer 0.05 M bei pH9.30 durchgeführt und basiert auf
der Bildung von unlöslichen Barbituratsalzen. Die Beziehung zwischen der Barbituratkonzentration
und dem Peak-Strom ist linear iiber die Konzentrationsskala von 4-1oOpm. Diese einfache und
spezifische Methode kann auch auf die Tablettenanalyse angewandt werden. Die Natur des
Elektrodenprozesses und der Mechanismus werden ebenfalis untenucht.
As barbiturates are used so extensively in clinical practice as depressants of the central nervous
system, it is important to develop a rapid, sensitive and reproducible method of determination.
Barbituric acid derivatives have been determined by using classical'.'), spectrophotometri?),
fluorimetric4) and chromatographi?*6) methods. Phenobarbital has been determined by AC
polarography in dosage forms'). The polarographic behaviour of some barbiturates like amobarbital,
barbital, barbituric acid, diallylbarbituricacid, pentobarbital and phenobarbital has also been studied
making use of AC polarography*). DC and AC polarography were chosen as methods of
determination of phenobarbital in nonaqueous mediag).A differential pulse polarographic method
has been developed for the determination of phenobarbital after nitration"). Differential pulse
polarography (d. p. p.) has been used to increase the accuracy of determination of phenobarbital and
N-alkyl phenobarbital mixtures").
In the present work we examined the d. p. p. behaviors of some barbituric acid derivatives in pure
and pharmaceutical forms.
+)
This work was presented at 1st International Symposium on Drug Analysis, Brussels, 1983.
0365-5233/86/0202-0149 $ûZ.SOM
Q VCH VerlagsgcscllschaftmbH,D-6940 Weinheim, 1986
150
Temizer and Solak
Arch. Pharm.
Results and Discussions
1. Selection of the supporting electrolyte
We used d. p. p. for the determination of eight pharmaceutically important barbitunc acid
derivatives"). The polarographic determination of these substances is based on the measurement of
anodic waves, corresponding to the formation of insoluble mercury saits"). The DC, tast and pulse
polarographicwaves of barbituric acid derivatives are not well-defined. The sensitivity of the analysis
was found to be low in these methods. These difficulties are reduced in d. p. p.
The changes of peak currents with pH for each derivative were examined by d. p. p. in different
acidic, basic and buffer solutions. In 0.1 N-NaOH barbituric acid derivatives are decomposed due to
In carbonate buffer, the reproducible peaks
the hydrolysis even during the time of de~xygenation'~).
could not be due to the slow rate of CO$-/HC@system to attain equilibrium. Methylphenobarbital
gave no peak in any of the solutions studied. For al1 other buffers, the observed peak merges int0 the
supporting electrolyte decay peaks below pH 7.0and above pH 12.0. Peak currents are dependent on
pH and the type of the buffer. Between pH7.0-12.0 peak currents of allobarbital have been shown in
Fig. 1. The peak current versus pH patterns were analogous for each derivative"). The maximum
peak currents for each derivative are in borat buffer for the Same barbiturate concentration. The
maximum peak heights are between pH9.C-10.0. Since the buffer capacity of borate buffer is
maximum at pH9.30, that is at the pK, of boric acid, 0.05 M-borate buffer at this pH was selected as
the best supporting electrolyte for the determination of barbiturates, as in DC polarography"). At
this pH the separability of barbiturate peak and electrolyte decay peak are also maximum.
7
a
9
10
11
12-
PH
F i g k Changes of peak currents of Allobarbital with pH in different buffer solutions. a) Citrate,
b) Phosphate, c) Britton-Robinson, d) Borate buffers.
2. The effect of variables on polarographic behaviors
For the investigation of limiting current characteristics, the changes of peak currents and peak
potentiais with mercury column height were studied at different barbiturate concentrations. The
limiting currents of them were found to be diffusion controlled at lower concentrations but
adsorptionai phenomena appeared as the concentration increased. This conclusion was also
confirmed by the effect of the temperature on peak currents. The temperature coefficients are found
to be 1.8% deg-' at lower and less than that at higher concentrations. The distortion on the
electrocapiliary curve ais0 indicates adsorption above mM concentration.
Polarographic Determination of Barbiturates
319/86
151
-
a
.
a
W
.-
o>
U
3
.-c
u
Q
E
Q
-m
+13.59
C
rn
._
u7
a
>
-0.2
0.0
+ 0'2
P o t e n t i a l ( V vs.SCE)
Fig. 2: Effect of concentration on the peak potentials and peak currents of Pentobarbital. a) Blank,
b) 19.6, c) 56.6 and d) 90.0 pM pentobarbital.
Peak potentials do not change with mercury head but depend on barbiturate concentration very
markedly (Fig. 2). The peak potentials shift toward more negative values as the concentration
increases for each derivative. But this shift is less at higher concentration (Fig. 3). The relationship
between the peak potentiai and the logarithm of Tncentration is linear. This behavior is a very
striking aspect of electrode processes based on mercury salt formation. The nature of the electrode
processes was also examined by observing the change of peak potential as a function of pH. E,-pH
plots are iinear with the same slopes for all derivatives within the experimentai error which were
verified by covariance analysis.
From the observations of the polarographic behaviors of barbitwates with pH,
temperature, mercury head, concentration and the type of the electrolyte it may be
concluded that the same electrode reaction mechanism is operative for al1 seven
denvatives. Since no current was observed at the dropping mercury electrode for
methylphenobarbital, it is also concluded that the mercury atoms are bound to the
barbiturates via the nitrogen atoms.
Considering the reaction center and the acidities of the 5 ,Idisubstituted derivatives
that depend only on the inductive effects of the substituents'@, "Linear Free Energy
Relationship" was applied and the relationship between pharmacological activities and
polarographic behaviors was also shown").
152
Temizer and Solak
20
riii
Arch. Pharm.
&O
Concentration
60
80 100
i JJM)
Fig. 3: Change of peak potentials of Barbituric Acid Derivatives with concentration. a) Phenobarbital, b) Amobarbital, c) Pentobarbital, d) Secobarbital, e) Sandoptal, f ) Ailobarbitai, g) Barbitai.
3. The analytica1 aspects
Barbiturates can be determined by d. p. p. which has been shown in Fig. 2. Similar
behaviors have been obtained for al1 other barbiturates studied except methylphenobarbital. Since the first reduction peak of the oxygen is in this region, the barbiturate peaks
are strongly affected by the dissolved oxygen in solution. Deoxygenation was carned out
by the passage of a nitrogen stream through the solution. The reduction of the oxygen is
prevented after a definite barbiturate concentration. The effect of the oxygen is
diminished for the concentration of 4.0 pM. So it can be concìuded that the lower limit of
detection is the concentration at which the effect of oxygen is prevented completely. As
can be seen iii Table 1,the d. p. p. method exhibits a very large linear concentration range
with good correlation coefficients. The differences in the lower and upper limits of
linearity for different barbiturates show the different adsorptional characters of the
derivatives.
Tabie 1: Characteristics of linear regression of calibration graphs for Barbituric Acid Derivatives in
0.05 M-borate buffer at p H 9.30 by d . p . p .
Compound
Barbitai
Amobarbital
Pentobarbital
Allobarbital
Sandoptal
Secobarbital
Phenobarbitai
'Number of data points
Linear
Na
Range (PM)
Slope
-
b4.pM-l
4.0- 90.0
4.3- 98.0
4.8-107,O
4.6- 96.0
4.2-100.0
4.8-110.0
5.2- 90.0
9
9
9
9
9
9
9
0.00316
0.00212
0.00095
0.00241
0.00174
0.00078
0.00066
Intercept
1
(PA)
0.02399
-0.01972
0.002821
-0.00527
-0.00014
0.00663
-0.00108
Cor.
Coeff.
0.9738
0.9144
0.9993
0.9965
0.9994
0.9996
0.9998
153
PoiaroaraDhic Determination of Barbiturates
319186
4. Analysk of pharmaceuticals
The application of the d. p. p. method of analysis to real samples was realized by the six
different commercially avdable pharmaceuticais (Table 2). They were analyzed by two
rnethods. The classicalmethods were taken from lit. which give lower results due to having
low precision and accuracy. In order to analyze them by d. p. p. they were dissolved in
0.003 N-NaOH without any clean-up procedure. The standard deviation was 1% or less.
It was observed that the other drug substances such as isoptine HC1, dextropropiophene
HCl, aminophenazone, trimethylxanthine, ergotamine tartarate and the additives present
in available commercial products did not interfere with the barbiturates.
Table 2: Analysis of Barbituric Acid Derivative containing Tablets
Compounds
determined
~~
Barbital
Pentobarbital
Allobarbitala
Allobarbitalb
F%enobarbitalc
Phenobarbitala
a tablet;
20.0
20.0
30.0
30.0
20.0
100.0
20.17
19.81
29.70
31.39
19.79
98.70
19.36
19.11
28.21
29.66
18.85
92.78
compnmée; dragee
Experimental Part
I. Reagents and Solutions
Samplesof barbital, amobarbital, pentobarbital, ailobarbital, sandoptal, secobarbital, phenobarbital
and methylphenobarbital were obtained from both the Centra1 Institute of Hygiene of Turkey and
World Health Organization. These substances were controiled for their purity and used without
further pwification. Chemicals for buffer preparations were reagent grade. Millimolar aqueous
solutions of barbiturates were freshly prepared in 0.002 N-NaOH.
2. Apparatus
A multipurpose polarographic analyzer which has been described in previous works, was used in this
experiment'*^"), The working electrode was a dropping mercury electrode which had an outflow
velocity of 2.27mg.s-' in 0.05 M-borate buffer at pH 9.30,0.00 volt vs SCE and a mercury head
pressure of 50 cm. A SCE and platinum wire have been used as reference and auxiliary electrodes. pH
measurements were carried out with a Corning Model 12Research pH meter. The purity of water was
controlled by a YSI model 31 conductivity bridge.
3. Polarographic conditions
The scanning was carried out with a rate of 2mV.s-l from -0.200 to +O.lOOV vs. SCE. The current
range was upto 500 nA.The drop timer was set at 1 s, the height of the mercury column was 50 cm and
the pulse amplitude was applied as 25 mV. The temp. of the cell was 20 f 0.1 "C.
154
Kiefer, Keppeler and De Clercq
Arch. Pharm.
References
1 S . A. Soliman, Y. A. Beltagy and I. M. Roushdi, J. Pharm. Pharmacol. 21, 44 (1969).
2 F. Dutrieux, M. Nonclero, C. Nys and Mrs. Laboureur, J. Pharm. Belg. 22,225 (1967).
3 L. R. Goldbaum, Anal. Chem. 24, 1604 (1952).
4 C. I. Miles and G. H. Schenk, Anal. Chem. 45, 130 (1973).
5 E. Brochmann-Hansen and T. Olawayi Oke, J. Pharm. Sci. 58,371 (1969).
6 R. F. Adams and F. L. Vandemark, Clin. Chem. N. Y. 22, 25 (1976).
7 N. G. Lordi, E. M. Cohen and B. L. Taylor, J. Am. Pharm. Assoc. Sci. Ed. 49, 371 (1960).
8 E. M. Cohen, Dissert. Abstr. 26,108 (1965).
9 A. L. Woodson and D. E. Smith, Anal. Chem. 42,242 (1970).
10 M. A. Brooks, J. A. F.de Silva and M. R. Hackman, Anal. Chim. Acta 64, 165 (1973).
11 P. Zuman, Proc. Analyt. Div. Chem. Soc. 1975, 199.
12 A. O. Solak and A. Temizer, J. Electroanal. Chem. 151, 101 (1983).
13 A. Temizer, J. Pharm. Belg. 37, 157 (1982).
14 E. R. Garret, J. Bojarski and G. J. Yakatan, J. Pharm. Sci., 60, 1145 (1971).
15 P.Zuman, J. Koryta and R. Kalvoda, Collect. Czech. Chem. Commun. 18, 350 (1953).
16 A.G. Briggs, J. E . Sawbridge, P. Tickle and J. M. Wilson, J. Chem. Soc. 7, 802B (1969).
[Ph 311
Arch. Pharm. (Weinheim) 319, 154-160 (1986)
Prodrugs of 5-Ethyl-2'-deoxyuridine,11')
Syntheses and Antiviral Activities of 5'- and 3'-Ester
Derivatives'")
Gebhard Kiefer+), Klaus Keppeler+)*)and Erik De Clercq++)
+)Research Laboratones of Robugen GmbH, PoBox266,7300Esslingen, West Germany and the
++)KatholiekeUniversiteit Leuven, Rega Instituut, Minderbroedersstraat 10, B-3000Leuven,
Belgium
Eingegangen am 17. Dezember 1984
With the aim of obtaining derivatives of the wel1 established antiherpes compound 5-ethyl2'-deoxyundine (1) (Aedurid', EtUdR, EDU), which are more lipophilic and therapeutically
superior, 5 ' - and 3'-ester derivatives of 1were synthesized. Tested in primary rabbit kidney cell
cultures against various strains of herpes simplex type 1 (HSV-1) and type 2 (HSV-2), al1 EtUdR
esters, with the exception of compounds 8 and W, proved almost as active as EtUdR itself, suggesting
that they were readily hydrolized.
+++) Dedicated to Apotheker ErnstMauz, managing director of Robugen GmbH, on the occasion of
his 85th birthday
0365-6233/86/0202-0154$ M.50/0
Q VCH Veriagsgesellschah mbH,D-6940 Weinheim, 1986
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