Oxidation of diclofenac sodium by diperiodatoargantate(III) in aqueous alkaline medium and its determination in urine and blood by kinetic methods

Article abstract of DOI:10.1002/kin.20486

The kinetics and oxidation of diclofenac sodium (DFS) by diperiodatoargentate(III) (DPA) in alkaline medium at 298 K and at a constant ionic strength of 0.60 mol dm^-3 were studied spectrophotometrically. The oxidation products were [2-(2,6-dicloro-phynylamino)- phenyl]-methenol and Ag(I), identified by LC-ESI-MS and IR spectral studies. The reaction between DFS and DPA in alkaline medium exhibits 1:1 stoichiometry. The reaction is first order in [DPA] and has a less than unit order dependence each in [DFS] and [alkali]. Increasing concentrations of IO₄- retard the reaction. The active species of DPA proposed to be monoperi- odatoargentate(III), and a mechanism is suggested. The rate constants involved in the different steps of the mechanism were determined and are discussed. The activation parameters with respect to a rate-limiting step of the mechanism were determined. The thermodynamic quantities were also determined. Using the oxidation of DFS by DPA, DFS was analyzed by kinetic methods in urine and blood sample. The proposed method enables DFS analysis in the range from 5.0 × 10^-5 to 5.0 x 10^-3 mol dm^-3.

Full text of DOI:10.1002/kin.20486

Oxidation of Diclofenac
Sodium by
Diperiodatoargantate(III) in
Aqueous Alkaline Medium
and Its Determination in
Urine and Blood by Kinetic
Methods
P. N. NAIK, S. A. CHIMATADAR, S. T. NANDIBEWOOR
P. G. Department of Studies in Chemistry, Karnatak University, Dharwad 580 003, India
Received 19 January 2009; revised 20 April 2009, 26 June 2009, 21 December 2009; accepted 4 January 2010
DOI 10.1002/kin.20486
Published online in Wiley InterScience (www.interscience.wiley.com).
ABSTRACT: The kinetics and oxidation of diclofenac sodium (DFS) by diperiodatoargentate(III)
(DPA) in alkaline medium at 298 K and at a constant ionic strength of 0.60 mol dm−3 were
studied spectrophotometrically. The oxidation products were [2-(2,6-dicloro-phynylamino)-
phenyl]-methenol and Ag(I), identified by LC-ESI-MS and IR spectral studies. The reaction
between DFS and DPA in alkaline medium exhibits 1:1 stoichiometry. The reaction is first order
in [DPA] and has a less than unit order dependence each in [DFS] and [alkali]. Increasing
concentrations of IO−4 retard the reaction. The active species of DPA proposed to be monoperi-
odatoargentate(III), and a mechanism is suggested. The rate constants involved in the different
steps of the mechanism were determined and are discussed. The activation parameters with re-
spect to a rate-limiting step of the mechanism were determined. The thermodynamic quantities
were also determined. Using the oxidation of DFS by DPA, DFS was analyzed by kinetic methods
in urine and blood sample. The proposed method enables DFS analysis in the range from 5.0 ×
10−5 to 5.0 × 10−3 mol dm−3
.
2010 Wiley Periodicals, Inc. Int J Chem Kinet 42: 336–346, 2010
ꢀ
C
INTRODUCTION
Diclofenac sodium (DFS), i.e., [o-[(2,6-dichloro-
Correspondence to: S. T. Nandibewoor; e-mail: stnandibewoor
@yahoo.com.
phenyl)amino]phenyl] sodium acetate, belongs to the
nonsteroidal anti-inflammatory drugs. There is a need
to develop a simple and economical method for the
assay of DFS in pharmaceutical preparations.
Supporting Information containing figures and an appendix is
available in the online issue at www.interscience.wiley.com.
c
ꢀ
2010 Wiley Periodicals, Inc.

OXIDATION OF DICLOFENAC SODIUM BY DIPERIODATOARGANTATE(III)
337
Diperiodatoargentate(III) (DPA) is a powerful ox-
idizing agent in alkaline medium with the reduction
potential [1] 1.74 V. It is widely used as a volumetric
reagent for the determination of various organic and in-
organic species [2]. Jayaprakash Rao et al. [3,4] have
used DPA as an oxidizing agent for the kinetics of ox-
idation of various organic substrates by generalizing
the DPA as [Ag (HL)L](x+1)−, where L is a periodate
with an uncertain number of protons and HL is a pro-
tonated periodate of an uncertain number of protons.
However, Kumar et al. [5–7] had made an effort to
give evidence for the reactive form of DPA in the large
scale of alkaline pH. In the present investigation, we
have obtained the evidence for the reactive species for
DPA in alkaline medium.
The present study deals with the title reaction to
investigate the redox chemistry of DPA in such a
medium, to identify the oxidation product of DFS, to
arrive at a plausible mechanism. Of the existing tech-
niques used for the determination of DFS, the potentio-
metric method [8] is less sensitive; spectrophotometry
[9], fluorometry [10], chromatography methods [11],
and recently, some electrochemical methods [12,13]
and the reversed-phase high-performance liquid chro-
matography (HPLC) method based on UV detection
[14] are laborious, expensive, and time consuming.
This has prompted us to develop a sensitive, accu-
rate, and economically viable technique for the deter-
mination of DFS in pharmaceutical preparations. The
method is based on oxidation of the drug by DPA.
was characterized by its UV spectrum, exhibited three
peaks at 216, 255, and 362 nm. These spectral features
were identical to those reported earlier for DPA [16].
The magnetic moment study revealed that the complex
is diamagnetic. The prepared compound was analyzed
[17] for silver and periodate by acidifying a solution
of the material with HCl, recovering and weighing the
AgCl for Ag, and titrating the iodine liberated when
excess KI was added to the filtrate for IO−4 . Thus the
obtained DPA was dissolved in water and was used for
the required [DPA] in the reaction mixture.
Kinetic Procedure
The kinetic measurements were performed with a Var-
ian CARY 50 Bio UV–vis spectrophotometer. The re-
action was followed under pseudo-first-order condi-
tions where [DFS] ꢁ [DPA] at 25
0.1◦C, unless
otherwise specified. Reaction was initiated by mixing
the DPA solution with diclofenac sodium solution, the
latter also containing the required concentrations of
KNO3, KOH, and KIO4 (see the Materials and Meth-
ods section). Reaction progress was followed spec-
trophotometrically at 360 nm by monitoring the de-
crease in absorbance of DPA, using the known molar
absorbance index [18], ε = 13, 900 100 dm3 mol−1
cm−1. It was verified that there is a negligible in-
terference from other species present in the reaction
mixture at this wavelength. The pseudo-first-order rate
constants (kobs) were determined from the slopes of
plots log(absorbance) versus time (Supporting Infor-
mation Fig. I). The equation used for the calculation of
kobs was −2.303 × slope. The plots were linear up to
85% completion of reaction. The rate constants were
EXPERIMENTAL
Materials and Reagents
All chemicals used were of reagent grade, and dou-
ble distilled water was used throughout the work.
DFS (IP) was dissolved in water, and concentration
was checked [8] potentiometrically. KNO3 and KOH
(BDH, Bangalore, India) were used to maintain ionic
strength and alkalinity of the reaction, respectively.
Aqueous solution of AgNO3 was used to study the
product effect, Ag(I). A stock standard solution of IO4−
was prepared by dissolving a known weight of KIO4
(Riedel-de Haen, Seelze, Germany) in hot water and
was used after 24 h to attain equilibrium. Its concen-
tration was ascertained iodometrically [15] at neutral
pH maintained using phosphate buffer.
Figure 1 Spectroscopic changes occurring in the oxidation
of diclofenac sodium by diperiodatoargantate(III) at 25◦C,
[DPA] = 5 × 10−5, [DFS] = 5 × 10−4, [OH−] = 0.50, and
I = 0.60 mol dm−3 with scanning time interval =1 min.
Preparation of DPA
DPA was prepared by oxidizing Ag(I) in the presence
of KIO4 as described elsewhere [16]. The complex
International Journal of Chemical Kinetics DOI 10.1002/kin

338
NAIK, CHIMATADAR, AND NANDIBEWOOR
reproducible to within 5%. The spectral changes dur-
ing the reaction shown in Fig. 1 clearly show the de-
crease in the DPA absorbance at 360 nm. It is evident
from Fig. 1 that the concentration of DPA is decreasing
by observing the absorbance at 360 nm. Since periodate
is also present in DPA, the possibility of oxidation of
diclofenac sodium by periodate in alkaline medium at
25◦C was checked. No significant reaction was found
under the experimental conditions. The effect of dis-
solved oxygen on the rate of reaction was checked by
preparing mixtures and carrying out the kinetic studies
in an atmosphere of nitrogen. No significant difference
between the results obtained under nitrogen and in the
presence of air was observed. In view of the ubiqui-
tous contamination by CO23−, the effect of added car-
bonate on the reaction rate was studied and found to
be negligible. Regression analysis of the experimental
data to obtain regression coefficient r and the stan-
dard deviation S, of points from the regression line,
was performed with the Microsoft office Excel 2003
program.
The oxidation product of diclofenac sodium
[2-(2,6-dicloro-phynylamino)-phenyl]-methenol was
isolated with the help of preparative TLC and charac-
terized by LC–ESI–MS, FTIR, and 1H NMR spectral
studies.
LC–ESI–MS analysis was carried out using reverse
phase HPLC system with a phenomenes C-18 column,
UV/–visible detector and series mass analyzer. 20 μL
of acidified reaction mixture was injected. The mobile
phase consisted of 10 mM ammonium acetate pH 3.0
(eluent A) and acetic acid (eluent B) at a flow rate
of 1 mL/min. Gradient elution was run to separate
substrate and reaction products. Gradient elution
ratios are 0 min/50% A and 50% B, 5 min/50% A
and 50% B, 15 min/30% A and 70%B, 17 min/30%
A and 70%B, 20 min/50% A and 50% B, and 22 min/
50% A and 50% B. LC–ESI–MS analysis indicated
the presence of two main products with molecular
ions of m/z at 273 (yield ca. 90%) and 598 (yield ca.
5%), respectively (Supporting Information Fig. II).
The molecular ion of diclofenac sodium is m/z 299.
The m/z at 598 corresponds to dimer product of DFS.
The product [2-(2, 6-dicloro-phynylamino)-phenyl]-
methenol was further confirmed by its characteristic
IR and 1H NMR spectrum. The disappearance of
the sharp band (peak) at 1695 cm−1 due to acidic
carbonyl in DFS confirms the product. A further
secondary amine (–NH) group observed around 3387
cm−1 in DFS remains in the product (Supporting
Information Fig. III). In 1H NMR (DMSO) spectrum,
the disappearance of the acidic OH band of DFS and
the appearance of the alcoholic hydroxyl proton triplet
band at 6.859 ppm confirm the product. Furthermore,
the secondary amine (–NH) proton singlet band
around 3.69 ppm and other aromatic proton bands in
DFS remain in the product, which disappears on D2O
exchange, confirming the formation of product [2-(2,
6-dicloro-phynylamino)-phenyl]-methenol (Fig. 2).
All these observations proved the formation of [2-(2,6-
dicloro-phynylamino)-phenyl]-methenol as a major
product. The dimer structure of DFS is as follows:
RESULTS
Stoichiometry and Product
Characterization
Different sets of reaction mixtures containing varying
ratios of DPA to diclofenac sodium in the presence of
a constant amount of OH−, KNO3 in reaction were
kept for 3 h in a closed vessel under nitrogen atmo-
sphere. The remaining concentration of DPA was es-
timated spectrophotometrically at 360 nm. Under the
condition where [DFS] > [DPA], the unreacted di-
clofenac sodium was estimated [9] as mentioned above.
The results indicate 1:1 stoichiometry for both the
reactions as given in Eq. (1). The main reaction prod-
ucts were identified as [2-(2, 6-dicloro-phynylamino)-
phenyl]-methenol and Ag(I).
COO –
CH2OH
–
+ [Ag(H3IO6)2]–
NH
+ OH
+ H2O
Cl
NH
(1)
Cl
Cl
Cl
2–
+ HCO3– + Ag(I) + H2IO63– +H3IO6 + 2H+
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OXIDATION OF DICLOFENAC SODIUM BY DIPERIODATOARGANTATE(III)
339
Cl
Cl
HO
O
HN
NH
O
OH
Cl
Cl
1.0 × 10−4 mol dm−3, and the constant kobs values in-
dicated that the order with respect to [DPA] was unity
(Table I). This was also confirmed by linearity and par-
allelism of the plots of log (absorbance) versus time
up to 85% completion of the reaction (Supporting In-
formation Fig. I). The [DFS] was varied in the range
1.0 × 10−4 to 1.0 × 10−3 mol dm−3 at 25◦C. The kobs
values increased with the increase in [DFS] (Table I)
Reaction Orders
The reaction orders were determined from the slope of
log kobs versus log(concentration) plots (Supporting In-
formation Fig. IV) by varying the concentrations of one
reactant at a time while keeping all other concentrations
andconditions constant except DPA concentration. The
[DPA] was varied in the range from 1.0 × 10−5 to
Figure 2 1H NMR spectra of the product of oxidation of diclofenac sodium by diperiodatoargantate(III).
International Journal of Chemical Kinetics DOI 10.1002/kin

340
NAIK, CHIMATADAR, AND NANDIBEWOOR
Table I Effect of Variation of Diperiodatoargantate (III), Diclofenac Sodium, and Alkali Concentrations on the
Oxidation of Diclofenac Sodium by Alkaline Diperiodatoargantate(III) at 25.0◦ C, I = 0.6 mol dm−3
[DPA] × 105
[DFS] × 104
[OH−] × 101
[IO−4 ] × 105
k
obs × 104
k
cal × 104
(mol dm−3
)
(mol dm−3
)
(mol dm−3
)
(mol dm−3
)
(s−1
)
(s−1
)
1.0
3.0
5.0
8.0
10
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
1.0
1.0
1.0
1.0
1.0
7.30
7.16
7.38
7.14
7.20
7.0
7.0
7.0
7.0
7.0
5.0
5.0
5.0
5.0
5.0
1.0
3.0
5.0
8.0
10
5.0
5.0
5.0
5.0
5.0
1.0
1.0
1.0
1.0
1.0
2.20
5.30
7.38
8.80
9.80
2.1
5.0
7.0
8.9
9.8
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
0.5
0.8
1.0
3.0
5.0
1.0
1.0
1.0
1.0
1.0
1.88
2.56
3.21
6.07
7.38
1.8
2.5
3.1
5.8
7.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
1.0
3.0
5.0
8.0
10.0
7.38
4.25
2.99
2.06
1.71
7.0
4.0
2.8
1.9
1.5
and found an apparent less than unit order dependence
on [DFS]. The effect of alkali on the reaction rate was
studied in the range of 0.05–0.50 mol dm−3. The rate
constants increased with increasing [OH−] (Table I),
and the order was found to be less than unity.
polymer precipitate in methanol suggests a participa-
tion of free radicals in the reaction.
Effect of Temperature
The influence of temperature on the rate of reaction
was studied at 20, 25, 30, and 40˚C. The rate constants
(k) of the slow step of Scheme 1 were obtained from the
intercepts of the plots of 1/kobs versus 1/[DFS] at 20,
Effect of Periodate and Added Products
In the reaction, the periodate concentration was var-
ied from 1.0 × 10−5 to 1.0 × 10−4 mol dm−3 at
constant [DPA], [DFS], and ionic strength. It was ob-
served that the rate constants decreased by increasing
[IO−4 ] (Table I). Initially added products, Ag(I) and
[2-(2, 6-dicloro-phynylamino)-phenyl]-methenol did
not have any significant effect on the rate of reaction.
25, 30, and 40˚C and were calculated as 1.34 × 10−3
,
1.65 × 10−3, 2.22 × 10−3, and 4.60 × 10−3
s
−1. The
energy of activation and the other activation parameters
were evaluated from the Arrhenious plot of log k ver-
sus 1/T , and the values of the energy of activation, en-
thalpy of activation ꢀH#, entropy of r activation ꢀS#,
and free energy of activation ꢀG# were calculated as
47.7 kJ mol−1, 45.2
2 kJ mol−1, −146
Effect of Ionic Strength (I) and Dielectric
Constant of the Medium (D)
3 J K−1 mol−1, and 88.8 k J mol−1, respectively.
It was found that ionic strength and dielectric constant
of the medium had no significant effect on the rate of
reaction.
DISCUSSION
Ag(III) species (two electron-oxidant) due to its strong
versatile nature prompted studies on the kinetics of
oxidation of various organic and inorganic substrates
in late twentieth century. Among the various species
of Ag(III), Ag(OH)4−, diperiodatoargentate(III), and
ethylenebis (biguanide) silver(III) (EBS) are of maxi-
mum attention to the researchers due to their relative
Polymerization Study
The participation of free radicals in the reaction was
carried out according to the literature [18]. The reac-
tion mixture to which a known quantity of acrylonitrile
scavenger had been added initially, and the resulting
International Journal of Chemical Kinetics DOI 10.1002/kin

OXIDATION OF DICLOFENAC SODIUM BY DIPERIODATOARGANTATE(III)
341
K1
[Ag(H3IO6)2]– + OH–
[Ag(H 2IO6) (H3IO6)]2–+ H2O
K2
[Ag(H2IO6) (H 2O)2]+ [H3IO6]2–
[Ag(H2IO6) (H 3IO6)]2–+ 2H2O
COO –
Cl
H
N
K3
Complex(C)
+ [Ag(H2IO6)(H2O)2]
Cl
.
CH2
k
+ [AgOH]+ + HCO3 + H2IO63– +2H+
–
Complex(C)
NH
slow
Cl
Cl
.
CH2
CH2OH
Ag(I)
+
+ [AgOH]+
NH
Fast
NH
Cl
Cl
Cl
Cl
Scheme 1
stability. The stability of Ag(OH)4− is very sensitive
toward traces of dissolved oxygen and other impu-
rities in the reaction medium whereupon it had not
drawn much attention. However, the other two forms
of Ag(III) [3–7,19,20] are considerably stable; the DPA
is used in highly alkaline medium, and EBS is used in
highly acidic medium due to the considerable stability
of DPA and EBS in the respective media.
The water-soluble silver(III) periodate complex is
reported [16] to be [Ag(IO6)2]7−. However, in an aque-
ous alkaline medium and at a high pH range as em-
ployed in the study, periodate is unlikely to exist as
IO56− (as present in the complex) as is evident from
its involvement in the multiple equilibria (2)–(4). Such
protolytic equilibria have been described for aqueous
periodate chemistry [21,22]
be H3IO26− and H2IO63−. At higher concentrations,
periodate tends to dimerize [1]. However, the for-
mation of this species is negligible under conditions
employed for kinetic studies. On the contrary, in their
recent studies the authors [3,4] have proposed the DPA
as [Ag(HL)2]x− in which L is a periodate with un-
certain number of protons and HL is a protonated pe-
riodate of uncertain number of protons. This can be
ruled out by considering the alternative form [21] of
IO−4 at pH > 7, which is in the form of H3IO26− and
H2IO36−. Hence, DPA could exist as [Ag(H3IO6)2]− or
[Ag(H2IO6)2]3− in alkaline medium. Under the present
conditions, diperiodatoargentate(III) may be depicted
as [Ag(H3IO6)2]−. The similar speciation of perio-
date in alkali was proposed [23] for diperiodatonicke-
late(IV).
Since the rate of reaction was enhanced by [OH−],
the added periodate retarded the rate, and the reaction
had first-order dependence on [DPA] and fractional
order dependence on [DFS]; a mechanism (Scheme 1)
has been proposed that explains all other experimental
observations.
−
+
H5IO6
H IO + H
3
Ka = 5.1 × 10−4
(2)
(3)
ꢁ
ꢂ
4
6
H4IO−
H IO2− + H+ Kβ = 4.9 × 10−9
ꢁ
ꢂ
6
6
H3IO2−
H IO3− + H+ KY = 2.5 × 10−12 (4)
ꢁ
ꢂ
2
6
6
In the prior equilibrium step 1, the [OH−] deproto-
nates the DPA to give a deprotonated diperiodatoargen-
tate(III). In the second step, displacement of a ligand,
The protonated form of periodate, H5IO6, exists in acid
medium and as H4IO−6 at pH 7. Under the present al-
kaline conditions, the main species are expected to
International Journal of Chemical Kinetics DOI 10.1002/kin

342
NAIK, CHIMATADAR, AND NANDIBEWOOR
periodate, takes place to give free periodate, which
is evidenced by the decrease in the rate with the in-
crease in the concentration of periodate (Table I). It
may be expected that a lower Ag(III) periodate species
such as monoperiodatoargentate(III) (MPA) is more
important in the reaction than the DPA. The inverse
fractional order in [H3IO6]2− might also be due to this.
In the prerate determining stage, this MPA combines
with a molecule DFS to give a complex, which decom-
poses in a slow step to give an intermediate product
Ag(II) and a free radical derived from DFS. This free
unique isobestic point, observed at 426 nm, indicates
the presence of a single complex [24]. The Michaelis–
Menten plot proved the complex formation between
oxidant and reductant, which explains the less than
unit order in [DFS]. Spectroscopic evidence for the
complex formation between oxidant and substrate was
obtained from UV–vis spectra of DFS (5.0 × 10−4),
DPA (5.0 × 10−5), [OH−] (0.50) mol dm−3, and a mix-
ture of both. A bathochromic shift of about 4 nm from
336 to 340 nm in the spectra of DPA was observed.
The structure of MPA and complex (C) is given below.
O
O
OH
HO
I
O
O
O
O
O
C
O
Ag
OH
HO
I
OH2
H2O
O
O
Ag
Cl
NH
H2O
OH2
Cl
Monoperiodatoargentate(III)
radical of DFS combines with Ag (II) species in a fast
Complex (C)
The rate law for Scheme 1 could be derived as
d[DPA]
kK1K2K3[DPA][DFS][OH−]
H3IO26− + K1[OH−] H3IO6 + K1K2[OH−] + K1K2K3[OH−][DFS]
Rate = −
= ꢀ
ꢁ
ꢀ
2−ꢁ
dt
step to give a [2-(2,6-dicloro-phynylamino)-phenyl]-
methenol. When DFS was reacted with a pseudo-
which explains all the observed kinetic orders of dif-
ferent species.
kK1K2K3[DFS][OH−]
H3IO26− + K1[OH−] H3IO6 + K1K2[OH−] + K1K2K3[OH−][DFS]
kobs = ꢀ
ꢁ
ꢀ
2−ꢁ
(5)
The rate law (5) can be rearranged into the following
form, which is suitable for verification:
first-order excess of DFS, a single complex formation
reaction was observed and expected. Under these con-
ditions, a 1:1 DPA(III):DFS complex is formed by
chelation of an DPA molecule at the carboxyl group of
DFS. Spectrophotometric titrations showed the com-
plex formation (Fig. 1). A decrease in the DPA ab-
sorption band at 360 nm is accompanied by the si-
multaneous increase in a unique absorption at 450 nm
(5), which is ascribed to the 1:1 DPA:DFS complex. A
ꢀ
ꢁ
H3IO26−
kK1K2K3[OH−][DFS]
1
kobs
=
ꢀ
ꢁ
H3IO26−
1
1
+
+
+
(6)
kK2K3[DFS] kK3[DFS]
k
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OXIDATION OF DICLOFENAC SODIUM BY DIPERIODATOARGANTATE(III)
343
5000
4000
3000
2000
1000
0
constant K1 is far greater than K2. This may be at-
tributed to the greater tendency of DPA to undergo de-
protonation compared to the formation of hydrolyzed
species in alkaline medium.
The thermodynamic quantities for the different
equilibrium steps, shown in Scheme 1, can be eval-
uated as follows: The DFS, H3IO26−, and hydroxide
ion concentrations as given in Table I were varied at
293, 298, 303, and 313 K. The plots of 1/kobs versus
1/[DFS], 1/kobs versus [H3IO6]2−, and 1/kobs versus
1/[OH−] should be linear as shown in Fig. 3. From the
0
2000
4000
6000
8000
10000
12000
slopes and intercepts, the values of K1 (dm3 mol−1
)
×
dm3 mol–1
(a)
1/ [DFS]
were calculated as 0.54, 0.47, 0.34, and 0.17, respec-
tively. In the same manner, K2 × 104 (mol dm−3
)
6000
5000
4000
3000
2000
1000
0
values were calculated as 0.15, 0.26, 0.71, and 2.90,
and K3 × 10−3 (dm3 mol−1) values were calculated as
6.28, 2.21 × 10−3 dm3 mol−1, and 0.71, respectively, at
different temperatures. A van’t Hoff’s plot was drawn
for the variation of K1 with temperature (i.e., log K1
vs. 1/T ), and the values of the enthalpy of reaction
ꢀH, entropy of reaction ꢀS, and free energy of re-
action ꢀG were calculated as −45.0 kJ mol−1, −158
J K−1 mol−1, and 1.90 kJ mol−1, respectively. In the
same manner, thermodynamic quantities for K2 were
calculated as 116 kJ mol−1, 302 J K−1 mol−1, and
26.1 kJ mol−1 and thermodynamic quantities forK3
0
5
10
15
20
25
1/[OH–] × dm3 mol–1
(b)
7000
6000
5000
4000
3000
2000
1000
0
were calculated as −85.5 kJ mol−1, −218 J K−1 mol−1
,
and −20.8 kJ mol−1, respectively. A comparison of the
thermodynamic quantity obtained from K2 values with
those obtained for the slow step of the reaction shows
that these values mainly refer to the rate-limiting step,
supporting the fact that the reaction before the rate-
determining step is fairly slow and involves high acti-
vation energy [26]. The values of ꢀS= and ꢀH= were
both favorable for electron transfer processes. The fa-
vorable enthalpy was due to release of energy on solu-
tion changes in the transition state. The high negative
value of ꢀS= (−146.1 J K−1 mol−1) suggests that the
intermediate complex is more ordered than the reac-
tants [27]. The observed modest enthalpy of activation
and a higher rate constant for the slow step indicate that
the oxidation presumably occurs via an inner-sphere
mechanism. This conclusion is supported by earlier
observations [28,29]. The negligible effect of ionic
strength and dielectric constant on the rate explains
qualitatively the reaction between negatively charged
ion and a neutral molecule [30], as shown in Scheme 1.
0
2
4
6
8
10
12
[H3IO42–] ×105 mol dm
–3
(c)
Figure 3 Verification of rate law (5) in the form of (6) for
the oxidation of DFS by diperiodatoargentate(III). (a) 1/k
obs
versus 1/[DFS], (b)1/k
versus 1/[OH−], and (c) 1/k
obs
obs
versus [H3IO6]2−
.
According to Eq. (6), other conditions being con-
stant, the plots of 1/kobs versus [H3IO26−], 1/[OH−], and
1/[DFS] were linear as shown in Fig. 3. From the inter-
cepts and slopes of such plots, the reaction constants
K1, K2, K3, and k at room temperature were calcu-
lated as 0.465 dm3 mol−1, 2.65 × 10−5 mol dm−3
,
4.42 × 103 dm3 mol−1, and 1.65 × 10−3
s
−1, respec-
tively. The values of K1 and K2 obtained are also in
agreement with the values published in the earlier liter-
ature [25]. These constants were used to calculate the
rate constants and compared with the experimental kobs
values and found to be in a reasonable agreement with
each other, which fortifies Scheme 1. The equilibrium
DETERMINATION OF DICLOFENAC
SODIUM BY KINETIC METHODS
The initial rate, rate constant, constant concentration,
and constant time method were used for determining
International Journal of Chemical Kinetics DOI 10.1002/kin

344
NAIK, CHIMATADAR, AND NANDIBEWOOR
Table II Determination of Diclofenac Sodium by Different Kinetic Methods at 25◦C, I = 0.6 mol dm−3
Fixed-Time Method
Fixed Concentration Method
(Absorbance = 0.54)
1/t (s)
Rate-Constant
Method
[DFS] × 104
(t = 120 s)
(mol dm−3
)
Absorbance
k
obs × 104 (s−1
)
0.50
0.80
1.00
3.00
5.00
8.00
10.0
15.0
20.0
30.0
40.0
50.0
0.668
0.660
0.658
0.625
0.602
0.568
0.552
0.499
0.452
0.448
0.428
0.415
0.048
0.054
0.063
0.201
0.313
0.417
0.516
0.714
0.833
1.012
1.080
1.120
1.30
1.60
2.10
4.64
6.97
9.66
11.6
16.5
21.0
28.7
31.6
33.5
diclofenac sodium, and the best method was chosen
based on applicability, the slope of the calibration
graph, the intercept, and the correlation coefficient (r).
was drawn, which is linear and can be used as a cali-
bration graph and the flowing equation is obtained:
Absorbance = 0.664 − 109.51[DFS](r = 0.9914)
Initial Rate Method
The range of the diclofenac sodium concentrations giv-
ing the acceptable calibration graph with the above-
mentioned equation was limited, 5.0 × 10−5 to 2.0 ×
10−3 mol dm−3 (i.e., 14.80–590 μg/cm3), which could
be a disadvantage.
In this method, graphs of the rate (at the beginning of
the reaction) versus the diclofenac sodium concentra-
tion were not easy to obtain because the reaction was
fast. Thus, the tangents to the curves at zero were not
easy to draw. This method was therefore abandoned.
Rate Constant Method
Fixed Concentration Method
Pseudo-first-order rate constants were calculated for
diclofenac sodium concentrations in the range from
5.0 × 10−5 to 5.0 × 10−3 mol dm−3 and are presented
in Table II. A plot of Kobs versus [DFS] was drawn,
which is used as a calibration graph as shown in Fig. 4,
and the following equation was obtained:
A preselected value of the absorbance was fixed, and
the time was measured for different diclofenac sodium
concentrations (Table II). The reciprocal of time (1/t)
versus the initial concentration of diclofenac sodium
was plotted, which could be used as a calibration graph
and the following equation was obtained:
kobs = 0.0002 + 0.9323 [DFS](r = 0.9937)
1/t = 0.0371 + 464.48 [DFS](r = 0.9907)
The range of diclofenac sodium concentrations giving
the most acceptable calibration graph with the above-
mentioned equation was 5.0 × 10−5 to 3.0 × 10−3 mol
dm−3 (i.e., 14.80–888.44 μg/cm3).
The range of the diclofenac sodium concentra-
tion giving the most acceptable calibration graph
with the above-mentioned equation was very limited,
5.0 × 10−5 to 1.5 × 10−3 mol dm−3 (i.e., 14.80–
444.22 μg/cm3), which could be a disadvantage.
Recommended Method
Fixed-Time Method
The above-mentioned kinetic procedure was applied
for a series of standard solutions of DFS (Table II).
The best correlation coefficient and high concentration
range of determination were obtained for the rate con-
stant method compared with the other kinetic methods.
A preselected time was fixed (120 s), and the ab-
sorbance was measured for different concentrations of
diclofenac sodium (Table II). A plot of the absorbance
versus the initial concentration of diclofenac sodium
International Journal of Chemical Kinetics DOI 10.1002/kin

OXIDATION OF DICLOFENAC SODIUM BY DIPERIODATOARGANTATE(III)
345
pharmacy, since it offers a distinct possibility for the
assay of a particular component in blood and urine.
40
30
20
10
0
Assay Procedure for Drug in Urine. A known amount
of DFS was added to 5 mL of urine sample. To this
was added 0.5 g of lead nitrate to precipitate the chlo-
rides present. The solution was filtered, and excess lead
present in the filtrate was removed by adding potas-
sium sulfate. The solution was again filtered. A suitable
amount of an aliquot was analyzed for the quantifica-
tion of DFS, as described for the pure drug.
k
0
0.001
0.002
0.003
0.004
0.005
0.006
[DFS] mol dm–3
Assay Procedure for Drug in Blood. One milliliter of
blood was spiked with a known amount of DFS before
the addition of sodium citrate. The citrated blood was
deprotonated with trichloroacetic acid and filtered. The
filtrate was diluted with distilled water to 100 mL in a
calibrated flask. An appropriate amount of an aliquot
was taken, neutralized with dilute sodium hydroxide
solution, and analyzed as described for the pure drug.
Figure 4 Plot of k versus [DFS] for diclofenac sodium
analysis by a kinetic method (the rate constant method); con-
ditions as mentioned in Table III.
obs
Hence, the rate-constant method was found to be more
applicable.
Application of the Method
The applicability of the rate constant method was ex-
amined as an assay of DFS in blood and urine sam-
ples. The results of urine and blood samples are given
in Table III and are compared with those of the official
method. This kinetic method has shown better recov-
ery than the reported method [8]. The performance of
the proposed method was judged by calculating the
recovery percentage from five replicate measurements
(Table III). The recovery percentage from five repli-
cate measurements was found to be more than 98%.
Analytical application of the proposed kinetic method
is for the determination of diclofenac sodium in urine
and blood samples. This aspect of the kinetic method
of determination is of major interest in analytical
CONCLUSION
Among the various species of Ag(III) in alkaline
medium, monoperiodatoargantate(III) was considered
to be the active species for the title reaction. Thermo-
dynamic quantities involved in the mechanism were
evaluated, and activation parameters with respect to
slow step of the reaction were computed. From an
analytical point of view, it is concluded that the de-
scribed procedure allows for the determination of di-
clofenac sodium in pure and pharmaceutical dosage
forms. Unlike the spectrofluorometer, as well as gas
chromatographic and HPLC procedures, the instru-
ment is simple and inexpensive. Its importance lies
Table III Analysis of Diclofenac Sodium in Blood and Urine Sample
Proposed Method
Potentiometric Method [8]
DFS Spiked
(μg/mL)
DFS Founda
(μg/mL)
Recovery
RSD%
DFS Founda
(μg/mL)
Recovery
RSD%
Sample
Blood 1
Blood 2
Blood 3
Blood 4
5.0
10.0
15.0
20.0
4.95
9.82
14.74
19.68
99.01 0.24
98.16 1.23
98.25 0.82
98.43 1.52
4.88
9.61
14.7
19.5
97.6 0.25
96.1 1.26
97.6 0.82
97.6 1.61
Urine 1
Urine 2
Urine 3
Urine 4
5.0
10.0
15.0
20.0
4.98
9.81
14.8
19.7
99.66 1.69
98.07 0.57
98.73 2.65
98.67 0.28
4.80
9.85
14.4
19.7
96.0 1.754
97.5 0.74
96.0 2.72
98.5 0.36
Rate constant method conditions as given in Table II.
aAverage of five determinations.
International Journal of Chemical Kinetics DOI 10.1002/kin

346
NAIK, CHIMATADAR, AND NANDIBEWOOR
in the chemical reaction upon which the procedure
is based, rather than sophistication of the instrument.
This aspect of the kinetic method of determination is
of major interest in analytical pharmacy.
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D
I
Dielectric constant of the medium
Ionic strength of the medium
K1 and K2 Equilibrium constants
k
Rate constant with respect to slow step
of the mechanism
Observed rate constant
Molar absorption coefficient
Change in free energy of reaction
Change in enthalpy of reaction
Change in entropy of reaction
Free energy of activation
Enthalpy of activation
Entropy of activation
Diperiodatoargentate(III)
Diclofenac sodium
Fourier transform infrared spectra
Proton nuclear magnetic resonance
Liquid chromatography electrospray
ionization tandem mass spectrometry
Thin-layer chromatography
Ultraviolet spectra
kobs
ε
ꢀG
ꢀH
ꢀS
ꢀG#
ꢀH#
ꢀS#
DPA
DFS
FT-IR
1H NMR
LC–ESI–
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International Journal of Chemical Kinetics DOI 10.1002/kin