Oxidation kinetics of simvastatin using cetyltrimethylammonium dichromate

Article abstract of DOI:10.1002/kin.20759

This article reports an attempt on the studies on resistance of oxidative stress by the prodrug, simvastatin (SV). Cetyltrimethylammonium dichromate has been used as a lipid compatible oxidant to study the oxidation kinetics of SV in organic media. The reaction undergoes via an ionic mechanism without any side product. The reaction is found to be acid catalyzed and sensitive to solvent polarity. The increase in the rate constant due to an increase in hydrophobicity (apolarity) of the solvent indicates the existence of a less polar transition state. Furthermore, the decrease in the rate constant due to an increase in [CTAB] suggests partitioning of the substrates and the oxidants into two different domains with different polar characteristics akin to a reversed micellar aggregates. Considering the above results and the thermodynamic parameters, a reaction mechanism has been proposed, wherein a complex formed at the interface of the two domains due to the reactant and the oxidant in a fast process decomposes to the products in a slow process in the nonpolar bulk.

Full text of DOI:10.1002/kin.20759

Oxidation Kinetics of
Simvastatin Using
Cetyltrimethylammonium
Dichromate
PRANGYA RANI SAHOO,1 SABITA PATEL,2 B. K. MISHRA1
1Center of Studies in Surface Science and Technology, School of Chemistry, Sambalpur University, Jyoti Vihar 768 019, India
2Department of Chemistry, National Institute of Technology, Rourkela 769 008, India
Received 5 May 2012; revised 22 August 2012; 13 September 2012; accepted 18 September 2012
DOI 10.1002/kin.20759
Published online in Wiley Online Library (wileyonlinelibrary.com).
ABSTRACT: This article reports an attempt on the studies on resistance of oxidative stress
by the prodrug, simvastatin (SV). Cetyltrimethylammonium dichromate has been used as a
lipid compatible oxidant to study the oxidation kinetics of SV in organic media. The reaction
undergoes via an ionic mechanism without any side product. The reaction is found to be acid
catalyzed and sensitive to solvent polarity. The increase in the rate constant due to an increase
in hydrophobicity (apolarity) of the solvent indicates the existence of a less polar transition
state. Furthermore, the decrease in the rate constant due to an increase in [CTAB] suggests
partitioning of the substrates and the oxidants into two different domains with different polar
characteristics akin to a reversed micellar aggregates. Considering the above results and the
thermodynamic parameters, a reaction mechanism has been proposed, wherein a complex
formed at the interface of the two domains due to the reactant and the oxidant in a fast process
decomposes to the products in a slow process in the nonpolar bulk. ꢀC 2012 Wiley Periodicals,
Inc. Int J Chem Kinet 1–7, 2012
formation of SV takes place at the heptanoic acid side
chain. It acts as an antioxidant and inhibits the oxi-
dation of low-density lipoproteins (LDL) [3] and also
decreases aldehyde production derived from lipopro-
tein oxidation [4]. SV treatment induced an increase
in autoantibodies against specific oxidized LDL anti-
gens [5].
The electrochemical detection of SV in the form
of drugs stems on its oxidation behavior in the pres-
ence of a multiwalled carbon nanotubes–dihexadecyl
hydrogen phosphate composite modified glassy carbon
electrode [6]. SV, on various stress degradation, such
as acid and base hydrolysis, oxidation by hydrogen
INTRODUCTION
Simvastatin (SV) is a lactone prodrug used for the
treatment of hypercholesterolemia [1]. Following con-
version of this lactone prodrug to its hydroxyl acid
form, the compound is a potent competitive inhibitor
of HMGCoA reductase, the rate-limiting enzyme in
cholesterol biosynthesis [2]. The oxidative biotrans-
Correspondence to: B. K. Mishra; e-mail: bijaym@hotmail.com.
Supporting Information is available in the online issue at
www.wileyonlinelibrary.com.
C
ꢀ
2012 Wiley Periodicals, Inc.

2
SAHOO, PATEL, AND MISHRA
peroxide led to the formation of simvastatin acid and
dehydrated products, respectively [7].
trations. By analyzing the rate constants determined by
varying [substrate], [acid], and [CTADC] in the reac-
tion process, a suitable mechanism for the reaction has
been proposed. Earlier, SV was subjected to oxidative
degradation by using hydrogen peroxide to yield a vari-
ety of products through a free radical mechanism [20].
Cr(VI) oxidation of many biological substrates also
encountered free radical intermediate, and the reac-
tions become complicated. In most of the oxidations
by CTADC, no free radical mechanism has been pro-
posed. Thus the present study highlights the effect of
Cr(VI) oxidant on SV to get a clear picture of the ox-
idative stress on SV.
An onium ion, as the counterion for anionic oxi-
dants, makes a lot of difference in oxidation poten-
tial of the oxidant as well as to the oxidizing system.
It makes the oxidant lipid soluble, mild, and many a
time chemoselective [8,9]. Tailor-made oniums have
been used as the counterions, wherein heterocyclic
bases such as pyridine, quinoline, caffeine, imidazole,
and nicotine units become a part of the oxidant [8].
In different reaction conditions, these oxidants often
show biomimetic characteristics due to the counteri-
ons, which help in providing a microheterogeneous en-
vironment with different solubilization pockets for the
substrates as in the case of micelles, reversed micelles,
microemulsions, vesicles for artificial systems, and
proteins and lipid membranes in living systems [10].
Among these oxidants, Cr(VI) has been studied exten-
sively.
EXPERIMENTAL
Materials
CTADC was prepared by the method reported ear-
lier [21]. SV(I) was used without further purification.
Glacial acetic acid was used as a source of hydrogen ion
and was used without further purification. The organic
solvents used were purified by standard methods [22].
The surfactants, CTAB and SDS, were obtained from
Spectrochem (Mumbai, India) and were purified by
recrystallization from ethanol solution.
In our efforts in exploring some biomimetic ox-
idants to oxidize organic substrates in organic sol-
vents, we have reported the oxidation behavior of
cetyltrimethylammonium permanganate (CTAP) [11–
14], cerate (CTACN) [15], and dichromate (CTADC)
[10,16] toward various organic substrates. These are
inorganic oxidants with an organic amphipathic car-
rier, cetyltrimethylammonium (CTA+) ion, to carry
the oxidants into the organic (lipid) phase. However,
these oxidants are hydrophobic and thus support the ex-
istence of a tight ion pair of the cationic carrier and the
anionic oxidant in nonpolar medium [17]. In organic
solvents, CTAP oxidizes its carrier, CTA+, in a man-
ner similar to β-oxidation of fatty acids [11]. Other
aforesaid oxidants are found to be inert toward their
carrier. We have used CTAP and CTADC for oxidation
of cholesterol to yield a diol at the double bond [14]
and 7-dehydrocholesterol [10], respectively, while with
addition of acetic acid to CTADC in dichloromethane
(DCM) the product was found to be 5-cholesten-3-one.
CTADC is devoid of an acidic proton and thus is rela-
tively milder than other Cr(VI) oxidants [8]. In the ab-
sence of acid, CTADC exhibits some bizarre reactions
with nonconventional products. Aromatic amines are
found to yield corresponding diazo compounds [18],
and arylaldoximes yielded corresponding nitriles [19].
In this paper, we have made an attempt to inves-
tigate the oxidation behavior of CTADC toward the
prodrug, SV, in organic solvents. To follow up the ob-
jectives, the oxidation product was characterized and
kinetics were run in different media with varied polar-
ities and also in microheterogeneous systems, gener-
ated due to the presence of a cationic surfactant (CTAB:
cetyltrimethylammonium bromide) and anionic surfac-
tant (SDS: sodium dodecyl sulfate) at different concen-
Kinetic Measurements
The oxidation kinetics of SV by CTADC in the pres-
ence of acetic acid was monitored in different solvents
and surfactant systems spectrophotometrically at the
absorption maxima of CTADC (350 nm) by using a
Hitachi U3010 spectrophotometer with a thermostatic
cell holder attached to a water bath. The first-order rate
constant, kobs, was obtained from the linear (r = 0.99)
plot of log[oxidant] against time upto 75% completion
of the reaction in a pseudo-unimolecular condition by
keeping a large excess of SV. The values reported are
the average of triplicate runs and were reproducible
within 4% error.
Product Analysis
After keeping the reaction mixture of CTADC and SV
in proper composition for 24 h in DCM, the volume
of the reaction mixture was reduced to a pasty mass
under low pressure. Acetic acid was added to the re-
action mixture with CTADC as the oxidant. Then the
organic compounds from the pasty mass were extracted
by using diethylether in excess. On evaporation of the
ether, the products were subjected to column chromato-
graphic separation by using a mixture of ethyl acetate
International Journal of Chemical Kinetics DOI 10.1002/kin.20759

OXIDATION KINETICS OF SIMVASTATIN
3
Table I Effect of [SV], [CTADC], and [Acetic Acid] on
the Oxidation of SV by CTADC at 303 K in DCM
and toluene (1:2 v/v). On evaporation of the eluents
with a single spot in TLC, the isolated compound was
subjected to fast atom bombardment mass spectrom-
etry (FABMS), nuclear magnetic resonance (NMR),
and infrared (IR) analyses. The compound is proposed
to be the corresponding carbonyl compound (II).
[CTADC] [SV] [Acetic kobs × 104
Rate × 107
× 104 (M) (M) Acid] (M)
(s−1
)
(mol L−1 s−1 a
)
0.5
1
2
4
1
1
1
1
1
0.02
0.02
0.02
0.02
.005
0.01
0.04
0.02
0.02
0.02
4.86
4.86
4.86
4.86
4.86
4.86
4.86
6.48
3.24
1.62
17.27
11.13b
9.21
4.22
5.76
0.86
1.11
1.84
1.69
0.58
0.69
1.73
1.50
0.81
0.46
Stoichiometry
The stoichiometry of the reaction was determined by
performing the experiment at 303 K, under the con-
ditions with fixed [Oxidant] and varying [SV]. The
disappearance of Cr(VI) was followed until the ab-
sorbance values became constant, and then CTADC
was estimated after 48 h. The stoichiometry ratios are
found to be 1:2 for CTADC/SV.
6.91
17.27
14.97
8.06
1
4.61
aRate = kobs × [CTADC].
b104 kobs at 293, 298, and 308 K were found to be 6.53, 9.98, and
14.97 s−1, respectively.
RESULTS AND DISCUSSION
R2 = 0.964, F = 54, n = 10
(1)
Under reflux conditions, the solution of CTADC and
SV in DCM in the presence of acetic acid became
green, indicating the reduction of Cr(VI) to Cr(III). The
completion of the reaction was ascertained by moni-
toring the TLC of the reaction mixture. CTADC exists
as a contact ion pair in aqueous medium as well as in
organic solvents [17]. In the presence of acetic acid,
the dichromate ion becomes free from the grasp of the
quaternary onium ion due to the change in polarity of
the medium and also the probable substitution of the
onium ion by proton of acetic acid. Furthermore, acry-
lonitrile was added to the reaction mixture during the
reaction process. As no turbidity of the medium in the
reaction mixture was observed, the possibility of the
free radical mechanism was ruled out. The reaction ki-
netics of the oxidation reaction was monitored in the
presence of acid, and the kinetic data are presented in
Table I.
Using the regression model, the log kobs values
were calculated and plotted against the observed values
(Fig. 2). A linear plot without any outlier supports the
validity of the regression model.
Without acid, the reaction became too slow to mea-
sure. With increasing [acetic acid], the rate constant
increases linearly (Fig. 3). The reaction is found to
acid catalyzed with an uncatalyzed rate of 1.15 ×
10−4 s−1
.
In an earlier report on oxidation of cholesterol, non-
linearity with the Michaelis–Menten relationship of
the substrate with the kobs was observed, indicating a
complex mechanism for the oxidation reaction [10]. In
the present study, the molecularity was found to be in
decimal (Eq. (1)), indicating an occurrence of a com-
plex reaction mechanism, which may be proposed vide
infra (Scheme 1, where Q refers to CTA).
The acid-catalyzed oxidation of SV with CTADC in
DCM was found to increase linearly with an increase in
the concentration of SV (Fig. 1). To obtain a relation-
ship between the rate constants with the parameters
of the reaction condition, i.e., [substrate], [oxidant],
and [acid], log kobs values obtained in different condi-
tions were correlated with the above three parameters
through multiple regression analysis. The regression
model, thus obtained, is given by Eq. (1). The orders
with respect to [CTADC], [SV], and [acetic acid] are
found to be 0.634, 0.554, and 0.844, respectively:
log kobs = −5.114 ( 0.321) − 0.634( 0.074)
× log[CTADC] + 0.554( 0.074)log[SV]
+ 0.844 0.107 log[acetic acid]
Figure 1 Plot of 104 kobs vs. [SV] in the oxidation reaction
of CTADC with SV at 303 K.
International Journal of Chemical Kinetics DOI 10.1002/kin.20759

4
SAHOO, PATEL, AND MISHRA
Figure 2 Plot of observed log k vs. calculated log k using
the regression model equation (1).
Figure 4 Plot of 104 kobs vs. [CTADC] in the oxidation of
SV at 303 K in DCM.
due to oxidation seems to be a complex phenomenon
as shown below:
Cr(VI) + 2e → Cr (IV)
Cr(IV) + Cr(VI) → 2Cr(V)
Cr(V) + 2e → Cr(III)
Cr(VI) is initially reduced to Cr(IV), which sub-
sequently changes to Cr(V) with another Cr(VI). The
formation of Cr(III) is a result of two-electron reduc-
tion of Cr(V). The existence of Cr(IV) as the reduced
state in oxidation of benzyl alcohol by quinolinium flu-
orochromate has also been reported by Dave et al. [23]
The rate constant is found to decrease nonlinearly
with increasing [CTADC] (Fig. 4). Similar observa-
tions have been made for the oxidation reaction of
different substrates by CTADC in organic solvents.
Earlier, it has been rationalized by proposing the oc-
currence of a reversed micellar phenomenon during
the oxidation reaction [10]. This proposition was fur-
ther supported by a drastic decrease in the rate con-
stant with addition of CTAB (Table II), a reversed
Figure 3 Plot of 104 kobs vs. [acetic acid] in the oxidation
reaction of SV with CTADC at 303 K.
Scheme 1 can lead to the derivation of a rate equa-
tion (Eq. (2)):
d[C]
[Q2Cr2O7][H+][SV]
Rate = −
=k[C] = kK1K2
dt
Q+
(2)
Cr(III) is found in the reaction products during the
oxidation of various substrates by CTADC in organic
medium [10]. The existence of Cr(III) in the product
mixture is well established from the peak at 580 nm.
However, reaction kinetics could not be studied at this
wavelength due to nonreliability and low absorptivity
of the spectrum. The formation of Cr(III) from Cr(VI)
Table II Rate Constant of Oxidation of SV at Different
[CTAB] and [SDS] at 303 K in DCM ([CTADC] = 1 × 10−4
M, [SV] = 0.02 M, [Acetic Acid] = 4.86 M)
K1
[CTAB] ×
kobs × 104
[SDS] ×
kobs× 104
H+
+ QCr O H
+
Q2Cr2O7
+
QCr O H
+ Q
2
7
104 (M)
(s−1
9.6
)
104 (M)
(s−1
)
K2
k
SV
Complex (C)
2
7
1
5
10
20
–
1
5
10
15
50
17.66
36.08
46.06
58.73
74.46
5.76
3.45
2.30
–
Complex (C)
Product
Rate-determining step
Scheme 1
International Journal of Chemical Kinetics DOI 10.1002/kin.20759

OXIDATION KINETICS OF SIMVASTATIN
5
Table III Observed Rate Constants for the Oxidation
micelle-forming surfactant. The spherical reversed mi-
celle has various localization sites, including the po-
lar inner core, where the ionic oxidant is partitioned
more. Substrate, being nonpolar in characteristics, par-
titioned to the bulk and remains away from the reactive
oxidant. With an increase in [CTADC], the inner po-
lar core may assume a larger interfacial area so that
the substrate can, relatively, be more in contact with
the polar oxidant to facilitate the complexation of the
SV and Cr(VI). Owing to the decrease in the polarity
of the complex compared to the reactants, it is parti-
tioned to nonpolar bulk and, therein, dissociates to the
product. The larger the interfacial area, the less will be
the partitioning leading to decrease in the rate. CTAB
can form spherical micelle in aqueous medium and re-
versed micelle in nonaqueous medium. The decrease
in the rate constant may be attributed to the enhanced
reversed micellization in the presence of CTAB, which
provides a common counterion with CTADC for the
formation of reversed micelle.
Furthermore, as the reaction is acid catalyzed and
the interface due to CTA+ is positively charged which
repels the proton, the rate is retarded. This proposition
gets further support from the rate enhancement due
to the addition of SDS, an anionic surfactant (Fig. 5).
SDS is inert toward CTADC and provides an anionic
environment to the reactant either through mixed mi-
cellization or through a reversed micellar aggregate,
which can provide an anionic interface for the interac-
tion between the proton, dichromate, and SV.
Reaction of SV in Various Organic Solvents at 303 K,
[CTADC] = 1 × 10−4M, [SV] = 0.02 M, and [Acetic Acid]
= 4.86 M
S. No.
Solvent
Dioxan
Ethyl acetate
Acetone
Acetonitrile
Benzene
Toluene
kobs × 104 (s−1
)
1
2
3
4
5
6
7
8
9
6.91
8.44
8.06
5.76
13.43
15.74
11.13
17.66
19.96
Dichloromethane
Chloroform
Carbon tetra chloride
To investigate the effect of environment on the re-
action mechanism, nine organic solvents with different
polarities were used as reaction medium. CTADC was
found to be stable in all these solvents in the presence
of acetic acid for more than 24 h. The rate constant
is found to be highly sensitive to change in polarity
of the solvents (Table III). To elucidate the character-
istics of the transition state of the reaction, the rate
constants were plotted against various solvent param-
eters such as cation-binding (A) and anionic-binding
(B) capacity, dielectric constant, π*, dipole moment,
and log P (where P being the partition coefficient of
the substrate between octanol and water indicating the
nonpolar characteristics of the solvents). The plots of
the rate constants with all the polarity parameters de-
lineate scattered relationship indicating the transition
state to be sensitive to polarity without any specific
trend. However, from the linear relationship of these
parameters with the rate constants, the solvents can
be classified into dipolar aprotic solvents (acetonitrile,
dioxane, ethyl acetate, and acetone) and nonpolar sol-
vents (benzene, toluene, carbon tetrachloride, chloro-
form, and DCM). In some corelationships, DCM is
found to be in the boarder line of the classification.
With the increasing dipole moment or dielectric con-
stant of the solvent, in most of the cases, the rate con-
stant decreases. In cognizance of this, the rate constant
increases with increasing log P value of the solvent
(Fig. 6). These observations support the formation of
a relatively less polar transition state compared to the
polarity of the reactants.
The rate law as derived in Eq. (2) gets support from
the above observations. With increasing [CTADC],
[acetic acid], and [substrate], the rates of the reaction
(as mentioned in Table I) increase linearly. Similarly,
the rate of reaction decreases with increasing [CTA].
The plot of rate vs. 1/[CTA] is also found to be linear
(R2 = 0.99).
The thermodynamic parameters such as ꢀH#, ꢀS#,
and ꢀG# were calculated for the oxidation of SV with
CTADC in the presence of 4.86 M acetic acid by using
Arrhenius and Eyring equations and are found to be
36.5 1.4 kJ mol−1, –181.1 6.9 J K−1, and 91.4
3.5 kJ mol−1, respectively. A high negative value
Figure 5 Plot of 104 kobs vs. [surfactant] for the oxidation
reaction of SV with CTADC at 303 K.
International Journal of Chemical Kinetics DOI 10.1002/kin.20759

6
SAHOO, PATEL, AND MISHRA
strate. The FABMS results of the carbonyl compound
with a (M – H)/z peak at 415.3 corroborate the struc-
ture of the product. The appearance of characteristics
IR band at 1577 cm−1 for β-diketone and disappear-
ance of 3549 and 1265 cm−1 for –OH substantiate the
oxidation of secondary –OH to corresponding carbonyl
one. Furthermore, the disappearance of the NMR peak
at 1.568 δ in the product is also an indicator of con-
version of the hydroxyl group to a corresponding car-
bonyl group. (The spectra of the reactant and product
are available as Supporting Information.)
Figure 6 Plot of 104 kobs vs. log P for the oxidation reaction
of SV with CTADC at 303 K .
CONCLUSION
SV is an established prodrug used in increasing the
level of high-density lipoproteins and acts at cellular
surface exposed to various oxidants. SV undergoes ox-
idative degradation by hydrogen peroxide through a
free radical mechanism. In the lipid system, metallic
oxidants like Cr(VI) can act to different substrates with
the help of an amphiphilic carrier. SV when interacts
with CTADC, Cr(VI) carried by cetyltrimethylammo-
nium ion, leads to the formation of the correspond-
ing carbonyl compounds catalyzed by an acid through
an ionic intermediate. The non–free radical reaction
leads to a mechanism with fewer or almost no side
of ꢀS# supports the proposal of the involvement of a
cyclic transition state [24].
From the above findings, a tentative mechanism has
been proposed (Scheme 2), wherein the CTADC equi-
librates with acetic acid to form the protonated dichro-
mate, which subsequently reacts with SV, giving rise
to a dichromate ester. The complex decomposes to the
reduced Cr(IV), which on further disproportionation
gives rise to stable Cr(III), and corresponding carbonyl
compound by α-hydrogen abstraction from the sub-
k
k
k
Scheme 2
International Journal of Chemical Kinetics DOI 10.1002/kin.20759

OXIDATION KINETICS OF SIMVASTATIN
7
products. Furthermore, the reaction is proposed to oc-
cur in an organized media where the partition of sub-
strates and oxidants into different domains retard the
rate of the reaction. The use of amphiphilic compounds
such as CTAB and SDS in the reaction media provides a
biomimic environment to understand the reaction pro-
cess. Thus CTADC is found to be an excellent model
oxidant to study the oxidative degradation of different
substrates in biological membranes.
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The authors thank the University Grants Commission
and Department of Science and Technology, New Delhi,
for financial assistance through the DRS and FIST pro-
grams. Financial assistance by CSIR, New Delhi, through
a major research project (no. 02(0030)/11/EMR-II) is also
acknowledged.
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Chem A 2009, 48, 1527.
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International Journal of Chemical Kinetics DOI 10.1002/kin.20759