Permanganate oxidative products of moxifloxacin, a fluoroquinolone drug: A mechanistic approach

Article abstract of DOI:10.1007/s11164-014-1862-8

The kinetics of oxidation of moxifloxacin (MOX) was studied spectrophotometrically by a well-recognized analytical reagent, permanganate (Mn(VII), in aqueous alkaline medium at a constant ionic strength. The reaction was first order in [Mn(VII)] and less than unit order both in [MOX] and [alkali]. Retarding effect on rate of reaction was observed with an increase in ionic strength. The effect of dielectric constant of the medium was also studied. The multiple m/z values of ESI-MS spectra prove the existence of various oxidative products of MOX. The main product was identified as 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(octahydro-2-oxopyrrolo[3,4-b] pyridin-6-yl)-8-methoxy-4-oxoquinoline-3-carboxylic acid. The other three oxidative products from MOX in the present study are similar to the oxidative products of other fluoroquinolones oxidations. However, the abnormally high values of m/z could be assigned to the permanganate complexes of the products, which are unusual in the non-metallic oxidation of MOX. A composite mechanism involving the monohydropermangante as the reactive species of the oxidant has been proposed. Activation parameters and thermodynamic parameters are calculated and the reaction constants involved in the different steps of the mechanisms are calculated.

Full text of DOI:10.1007/s11164-014-1862-8

Res Chem Intermed
DOI 10.1007/s11164-014-1862-8
Permanganate oxidative products of moxifloxacin,
a fluoroquinolone drug: a mechanistic approach
Seema S. Badi Suresh M. Tuwar
•
Received: 29 July 2014 / Accepted: 29 October 2014
Ó Springer Science+Business Media Dordrecht 2014
Abstract The kinetics of oxidation of moxifloxacin (MOX) was studied spectro-
photometrically by a well-recognized analytical reagent, permanganate (Mn(VII), in
aqueous alkaline medium at a constant ionic strength. The reaction was first order in
[
Mn(VII)] and less than unit order both in [MOX] and [alkali]. Retarding effect on
rate of reaction was observed with an increase in ionic strength. The effect of
dielectric constant of the medium was also studied. The multiple m/z values of ESI–
MS spectra prove the existence of various oxidative products of MOX. The main
product was identified as 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(octahydro-2-oxo-
pyrrolo[3,4-b] pyridin-6-yl)-8-methoxy-4-oxoquinoline-3-carboxylic acid. The other
three oxidative products from MOX in the present study are similar to the oxidative
products of other fluoroquinolones oxidations. However, the abnormally high values
of m/z could be assigned to the permanganate complexes of the products, which are
unusual in the non-metallic oxidation of MOX. A composite mechanism involving
the monohydropermangante as the reactive species of the oxidant has been proposed.
Activation parameters and thermodynamic parameters are calculated and the reac-
tion constants involved in the different steps of the mechanisms are calculated.
Keywords Moxifloxacin ꢀ Oxidation ꢀ Kinetics ꢀ Thermodynamics ꢀ Mechanism
Introduction
Permanganate is a well-known oxidizing agent that oxidizes most of the substrates
[
1–15], particularly organic substrates, viz., alkenes, alcohols, aldehydes, ketones,
S. S. Badi ꢀ S. M. Tuwar (&)
Department of Chemistry, Karnatak Science College, Dharwad 580 001, Karnataka, India
e-mail: sm.tuwar@gmail.com
S. S. Badi
e-mail: seema12984@gmail.com
123

S. S. Badi, S. M. Tuwar
carboxylic acids, poly-hydroxycarboxylic acids, sulfides, thiols, simple drugs,
antibiotics, steroids, etc. Hence, it is used generally as an analytical reagent. Since
permanganate is involved in five different oxidation [16] states, varying from ?7 to
?
2, the mechanism of oxidation of such substrates has a fascination of multiple
mechanisms. Nevertheless, it can be made a simple single equivalent oxidant (?7 to
6) in highly basic medium, bi-equivalent (?7 to ?5) in moderately basic, tri-
equivalent (?7 to ?4) in neutral, and in acidic media as penta-equivalent oxidant
?7 to ?2). Thus, its redox potential depends on pH of the media. In highly basic
?
(
medium, its redox potential is ?0.56 V, in slightly basic or in neutral ?1.23 V, and
in acid medium ?1.51 V. Depending upon the resistance of substrates towards
oxidation, pH of the reaction medium is maintained in permanganate oxidations.
Sometimes permanganate is used as an oxidizing agent in alkaline medium [17, 18]
to avoid the complexity in the mechanism of oxidation of drugs, particularly in
kinetic studies to understand the reaction path of such biologically active molecules.
Recently, permanganate has been successfully used for the in situ degradation of
many organic contaminants [19, 20]. The study was undertaken to understand fully
the kinetics and mechanism of oxidation of trichloroethylene, an important pollutant
present in ground water [21]. Hence, in the present study permanganate is used as a
single equivalent oxidant in establishing a reaction mechanism to understand the
oxidative paths of a new antibiotic, moxifloxacin.
Fluoroquinolones (FQs) like lomefloxacin, norfloxacin, ofloxacin, enrofloxacin,
ciprofloxacin etc., are a group of synthetic antibacterial agents that have been
widely used in human and veterinary medicines. FQs have in vitro and in vivo
activities against Gram-negative pathogens, Gram-positive cocci, aerobic intracel-
lular bacteria, atypical organisms, and anaerobic bacteria [22]. Moxifloxacin (MOX)
is a fourth-generation antibiotic of the class of fluoroquinolone, a modified form of
ciprofloxacin and enrofloxacin. Chemically, it is 1-cyclopropyl-6-fluoro-1, 4-dihy-
dro-8-methoxy-7- [(4aS, 7aS)-octahydro-6H-pyrrolo [3, 4-b] pyridin-6-yl]-4-oxo-3-
quinoline carboxylic acid. It is a broad-spectrum antibiotic agent used in the
treatment of bacterial infections (conjunctivitis) [23, 24]. The antimicrobial activity
depends upon the inhibition of DNA gyrase (bacterial topoisomerase II) and
topoisomerase IV, which regulate spatial arrangement of DNA in bacterial cells.
These proteins can cut both strands of the nucleic acid and rejoin them. Inhibiting
the activity of those enzymes by formation of irreversible complex drug/enzyme/
DNA disables the DNA synthesis and leads to the bacterial cell death [25, 26]. In
comparison with other fluoroquinolones, MOX presents a low profile of phototoxic
and central nervous system excitatory effects. It has been found to be effective in
acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis,
community-acquired pneumonia, skin and skin-structure infections, and intra-
abdominal infections including polymicrobial infections [27, 28].
Literature survey reveals [29] that many studies have been carried out on the
stability of MOX in the presence of metal ions like Cu(II), Fe(II), Zn(II), or
alimentary tract coating agent Al(III), which may result in some type of interaction
during compound application in medical care. Acid hydrolysis of FQs with the
presence of metal ions has been subjected to many studies, but MOX differs from
the other FQs at positions 7 and 8 of the molecule, and this difference has an
1
23

Permanganate oxidative products of moxifloxacin
influence on physicochemical properties and stability of the compound. Kinetic
evaluation of decomposition of MOX at 90 and 110 °C showed that the
decomposition of MOX in solutions in presence or in absence of metal ions
follows first-order kinetics. The presence of metal ions in MOX solutions increases
the rate of reaction and decreases the activation energy [29].
Due to the large usage, FQs could enter the environment via various routes
including municipal and industrial wastewater effluent, wastewater sludge, manure
from animal husbandry, and agricultural runoff. In recent years, studies from many
parts of the world including North America, Europe, and China have reported
frequent detection of FQs in surface water bodies at concentrations ranging from
non-detectable to around 50 ng/l [30–35] and in municipal wastewater at
concentrations as high as 700 ng/l in the influent and around 400 ng/l in the
effluent [30, 36–40] for individual FQ compounds. The most commonly detected
FQs include ciprofloxacin (CIP), norfloxacin (NOR), enrofloxacin (ENR), and
ofloxacin (OFL). This new generation of FQ, moxifloxacin (MOX), may also be
added up in the future. The presence of FQs in the aquatic environment, especially
in surface water that will become the source of potable supply, merits particular
concern because of potential health risks. FQs are potent antibiotics with low
minimal inhibitory concentrations (MICs) against a wide range of bacterial species
[
41]. Effective removal of FQs by water treatment processes is important to
minimize the possibility of antibiotic resistance development and other potential
health risks that may be associated with FQ residues in drinking water.
Hence, the growing usage of antibacterial agents and the potent risks of fostering
resistant pathogens and posing adverse effects on human health necessitate the
better understanding of transformation of these compounds in aquatic environment.
Wang et al. [42] have made use of ClO as an oxidant to understand the possible
2
products of FQs [42]. Recently, Zhang et al. [43] used MnO as a facilitating
2
oxidant in FQs oxidations for the detection of their oxidative products. However,
MOX was not used in their studies, neither in quantification nor in the kinetic
studies of oxidative degradation. Although Hubicka et al. [44] studied the
photochemical degradation of MOX, and Gouda et al. [45] used N-Bromosuccin-
imide, in the quantification of MOX and its products, no reaction paths have been
established for its oxidative products either from its pure form or from its
contaminants. Since permanganate has also been used for the treatment of surface
water on par with ClO , the present study is undertaken for the evaluation of
2
reaction paths of oxidation of MOX by alkaline permanganate.
Experimental
Materials
All chemicals used were of reagent grade and double-distilled water was used
throughout the study. Stock solution of MOX is prepared by dissolving required
quantity of sample; its purity was checked by its m. p (324–325 °C) [46] and TLC
for single spot. It is known that MOX undergoes decarboxylation [29]. Though the
123

S. S. Badi, S. M. Tuwar
decarboxylation is slow and takes place in acidic medium, rate of decarboxylation
was studied by measuring the kinetics runs with aqueous alkaline solution of MOX
with different ageing solutions. It was found that there were no differences in kinetic
results between fresh and aging solutions. However, fresh solutions were used in all
kinetic runs to avoid the error if any were to arise.
The solution of Mn(VII) was made by dissolving the required quantity of KMnO4
crystals in double-distilled water. It is known that KMnO is not a primary standard
4
solution, hence, it is standardized against sodium oxalate solution [47, 48]. Further,
it is preserved in darkness to avoid degradation due to exposure to sun light.
Potassium manganate Mn(VI) solution was prepared as described by Carrington and
Symons [49] as follows; an aqueous solution of potassium permanganate was heated
-
3
to boiling [100 °C in 8.0 mol dm KOH solution. The green-colored solution of
K MnO formed is characterized by its visible spectrum. The solution was
-1
2
4
3
-1
standardized spectrophotometrically at 608 nm (e = 1,530 ± 20 dm mol cm ).
This solution was used to study the product effect on rate of reaction. KOH and
KNO were used to provide the required alkalinity and to maintain the ionic
3
strength, respectively.
Kinetic measurements
Kinetic measurements were carried out with [MOX] excess over [Mn(VII)] under
pseudo-first-order condition, monitoring Mn(VII) consumption as absorption at its
kmax, 526 nm in a 1-cm quartz cell of a thermostated compartment of Specord-200
plus spectrophotometer setup with a Peltier accessory to control temperature at
3
03 K as a function of time. Earlier it was verified that there is no interference from
other reagents at this wavelength. The reaction was initiated by mixing previously
thermostated solutions of Mn(VII) and MOX, which also contained the required
quantities of KOH and KNO to maintain required alkalinity and ionic strength,
3
respectively. Application of Beer’s law for permanganate at 526 nm had earlier
3
-1
-1
3
been verified, giving e, 2,170 ± 30 dm mol
cm
(Lit. value = 2,200 dm
-
1
-1
mol cm ) [50]. First-order rate constants, kobs were calculated by the plots
log[Mn(VII)] versus time. In the course of measurements, the color of the solution
changed from violet to green. The spectrum of green solution was identified to that
2
-
of MnO4 (Mn(VI)). The results were reproducible within ± 3 %.
Product analysis
In order to identify the products formed in the reaction, known amounts of MOX
and Mn(VII) with different percentage composition (mol/mol) were allowed to react
-
3
completely at 303 K in 0.001 mol dm KOH. After completion of the reaction and
when [Mn(VII)] was in excess over MOX, the residual [Mn(VII)] in each case was
analyzed spectrophotometrically at 526 nm. The reduction product, Mn(VI), was
estimated by measuring its absorbance at 608 nm.
The oxidative product of MOX was identified as 1-cyclopropyl-6-fluoro-1,4-
dihydro-7-(octahydro-2-oxopyrrolo[3,4-b]pyridin-6-yl)-8-methoxy-4-oxoquinoline-
3
- carboxylic acid. It was analyzed as follows: the reaction mixture after completing
1
23

Permanganate oxidative products of moxifloxacin
the reaction was treated with 50 % methanol followed by acidification with HCl and
3
% acetonitrile and 1 % formic acid to make the solution in a positive-ion mode for
the LC–ESI–MS analysis. The solution was subjected to LC–ESI–MS analysis at
the rate of 5 ll/min with retention time 0.51–0.98 s in the applied voltage of 30 kV
with a glass micro-syringe. The nitrogen gas was used as nebulizer. The LC–ESI–
MS spectrum at positive electrode spray shows several peaks along with the
unreacted MOX (Fig. 1). Based on the m/z values, each peak is assigned to the
possible products as given in Scheme 2. Hence, it reveals that MOX on oxidation
gives different products. The major product was identified as 1-cyclopropyl-
6
-fluoro-1,4-dihydro-7-(octahydro-2-oxopyrrolo[3,4-b]pyridin-6-yl)-8-methoxy-4-
oxoquinoline -3-carboxylic acid. The stoichiometry for the main product can be
written as:
OCH3
O
N
OCH3
N
N
F
N
O
H
N
F
N
O
2
-
H
+
2 [MnO (OH)]
4
COO-
COO-
2MnO 2- + 2H O + other minor products
+
4
2
ð1Þ
1
00
F= 917.58
E= 478.29
MOX= 400.17
8
6
4
2
0
0
0
0
0
B= 449.43
D= 534.39
C= 415.15
A= 292.26
0
200
400
600
800
1000
m/z
Fig. 1 LC-ESI–MS spectrum of the products resulted due to the oxidation of moxifloxacin by
permanganate in aqueous alkaline medium
123

S. S. Badi, S. M. Tuwar
Results and discussion
Reaction order
The reaction orders were determined from the slopes of log kobs versus
-
log(concentration) plots varying the concentration of reductant and OH in turn
while keeping others constant. Since the first-order plots were linear up to 90 %, the
initial rate methods were not used for determining order of the reactants and other
species.
Effect of [Mn(VII)] and [MOX]
The effect of [Mn(VII)] on the reaction rate was studied by varying the [Mn(VII)]
-
5
-4
-3
from 4.0 9 10 to 6.0 9 10 mol dm at constant concentrations of MOX,
alkali, and ionic strength at a constant temperature (Table 1). It was observed that
slope of the plot of log (conc.) versus time remained constant for most of the
different [Mn(VII)] values. This was also confirmed from the linearity of plots of
log(absorbance) versus time to about 90 % completion of the reaction. Hence, the
order in [Mn(VII)] was considered as unity.
The effect of [MOX] on rate of reaction was studied at different temperatures in
-
4
-3
-3
the concentration range, 8.0 9 10 to 8.0 9 10 mol dm at all other reaction
concentrations constant (Table 2). The kobs values were increased with an increase
in [MOX] in all the temperatures. The order in [MOX] from the plot of log kobs
versus log [MOX] was found to be positive fractional order of average 0.70 without
much variation with temperature.
-
Effect of [OH ]
-
The influence of [OH ] on rate of reaction was studied by varying [KOH] from
-
.7 9 10 to 7.0 9 10 mol dm by keeping all other reaction concentrations
3
-3
-3
0
constant at temperature range from 303 to 318 K. It was observed that rates are
-
increased with increase in [OH ] (Table 3). The first-order plots were linear for all
-
the [OH ] in different temperatures and order from the plot of log k versus log
obs
-
OH ] was found to be positive fractional at a constant ionic strength of
[
-
.007 mol dm . In this case, the order with respect to [OH ] decreases from 0.61
3
-
0
to 0.39 for all the temperatures varied.
Effect of initially added product
The effect of initially added Mn(VI) on the rate of reaction was studied in the
-
5
-4
-3
concentration range of 1.0 9 10 to 1.0 9 10 mol dm at 303 K at constant
-
Mn(VII)] = 2.0 9 10 , [MOX] = 2.0 9 10 , [OH ] = 1.0 9 10 and ionic
4
-3
-
-3
[
strength = 7.0 9 10 mol dm . The added product did not influence the rate of
reaction.
-
3
-3
1
23

Permanganate oxidative products of moxifloxacin
Table 1 Effect of variation of
-
4
10 9 [MnO
-
4
3
10 9 [MOX] 10 9 [OH ] 10 9 kobs (s )
3
-
3
-1
-
], [MOX], and [OH ]
]
[MnO
4
-3
-3
-3
(mol dm )
(
mol dm
)
(mol dm
)
on oxidation of moxifloxacin
by permanganate in aqueous
alkaline medium at 303 K
a
b
Exptl.
Calc.
0
0
1
2
4
6
2
2
2
2
2
2
2
2
2
2
2
2
.4
.6
.0
.0
.0
.0
.0
.0
.0
.0
.0
.0
.0
.0
.0
.0
.0
.0
2.0
2.0
2.0
2.0
2.0
2.0
0.8
1.0
2.0
4.0
6.0
8.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.7
0.9
1.0
2.0
3.0
4.0
5.0
6.0
7.0
3.99
3.99
4.30
4.58
4.44
4.50
2.64
3.04
4.58
7.85
10.7
13.4
3.73
4.14
4.58
6.08
7.53
9.00
11.8
14.0
16.3
–
–
–
–
–
–
1.96
2.41
4.44
7.67
10.1
12.1
3.33
4.09
4.44
7.29
9.28
10.7
11.9
12.7
13.5
-
3
I = 0.007/mol dm
a
Experimental
b
Calculated: kobs were
calculated by using
-2
-1
s ,
2.0
2.0
k = 2.8 9 10
3
= 77.2 dm mol and
-1
K
K
1
2
2
3
= 13.1 9 10 dm mol
-1
2
.0
at 303 K in rate Eq. (11)
Effect of ionic strength and dielectric constant of the medium
-
The ionic strength of the reaction medium was varied between 0.2 9 10 and
2
-
2
-3
.0 9 10 mol dm with potassium nitrate at constant concentrations of alkali,
2
oxidant, and reductant at 303 K. It was found that as ionic strength increases, the
rate of reaction decreases. A plot of log kobs versus HI was linear with negative
slope -1.0 (Fig. 2).
Dielectric constant of the medium was varied by varying the percentage (v/v) of
t-butyl alcohol/H O content in the reaction mixture. Its effect was studied on rate of
2
reaction with all other conditions being constant. Since the D for various percentage
compositions was not available in literature, they were computed from the values of
the pure liquids as in earlier work [51]. In the reaction, kobs values were increased
with increasing the D (Fig. 2). Earlier, the reaction between t-butyl alcohol and
oxidant was studied and it was observed that there are no reactions between solvent
and oxidant.
Effect of temperature
The effect of temperature on the reaction rate was studied at various temperatures at
constant concentrations of oxidant and reductant, with other reaction conditions being
123

S. S. Badi, S. M. Tuwar
Table 2 Effect of variation of [MOX] on oxidation of moxifloxacin by permanganate in aqueous
alkaline medium at different temperatures
3
0 9 [MOX]
3
-1
1
10 9 kobs (s
)
-3
(
mol dm )
a
Exptl.
Calc. for
temp 303 K
b
3
03 K
308 K
313 K
318 K
0
1
2
4
6
8
.8
.0
.0
.0
.0
.0
2.64
3.04
4.58
7.85
2.72
3.39
5.65
9.87
13.5
15.5
0.78
3.16
3.92
6.69
10.9
13.8
16.2
0.73
-3
3.65
4.65
7.66
12.2
13.9
16.4
0.69
1.96
2.41
4.44
7.67
10.1
12.1
0.70
10.7
13.4
Order
0.70
-
4
-4
-
[MnO
] = 2.0 9 10 ; [OH ] = 0.001; I = 0.007/mol dm
a
Experimental
b
-2
-1
3
= 77.2 dm mol
-1
Calculated:
= 13.1 9 10 dm mol at 303 K in rate Eq. (11)
k
obs were calculated by using, k = 2.8 9 10
2
s
,
K
1
and
3
-1
K
2
-
Table 3 Effect of variation of [OH ] on oxidation of moxifloxacin by permanganate in alkaline medium
at different temperatures
3
0 9 [OH ]
-
3
-1
1
10 9 kobs (s
)
-3
(
mol dm )
a
Exptl.
Calc. for
temp 303 K
b
3
03 K
308 K
313 K
318 K
0
0
1
2
3
4
5
6
7
.7
.9
.0
.0
.0
.0
.0
.0
.0
3.73
4.14
4.58
6.08
7.53
9.00
5.55
5.71
5.94
8.69
11.6
12.8
13.5
15.2
15.8
0.51
8.19
8.26
8.65
11.8
13.4
15.3
16.2
16.9
17.2
0.42
11.2
11.9
12.2
13.5
16.7
17.5
19.1
20.0
20.6
0.39
3.33
4.09
4.44
7.29
9.28
10.7
11.9
12.7
13.5
0.61
11.8
14.0
16.3
Order
0.61
-
4
-4
-3
] = 2.0 9 10 ; [MOX] = 2.0 9 10 ; I = 0.007/mol dm
-3
[MnO
a
Experimental
b
-2
-1
3
= 77.2 dm mol
-1
Calculated:
= 13.1 9 10 dm mol at 303 K in rate Eq. (11)
k
obs were calculated by using, k = 2.8 9 10
2
s
,
K
1
and
3
-1
K
2
kept constant. The kobs values increased with increasing temperature (Table 4). Since
the reaction follows multistep mechanism, the reaction constants, viz., equilibrium
constants and rate constant of the slow step are involved. In order to arrive at the values
of such constants, the reaction was studied at various temperatures.
1
23

Permanganate oxidative products of moxifloxacin
Therefore, the effect of temperature on the rate of reaction was studied at 303,
-
08, 313, and 318 K by varying [MOX] and [OH ] in turn while others were kept
3
constant at constant concentrations of [Mn(VII)] and ionic strength (Table 2, 3).
From the slope of Arrhenius plot, log kobs versus 1/T, the activation energy, Ea was
=
=
=
calculated. Further, the other activation parameters, DH , DS , DG and log A
Table 5) were evaluated for overall reaction. On the hand, the rate constants (k) of
the slow step of Scheme 1 were obtained from the intercept of 1/kobs versus
/[MOX] for the various temperatures. The values ‘k’ calculated for slow step
(
1
remained almost constant with increase in temperature. Hence, activation param-
eters for the slow step are not calculated. This may be due to the involvement of two
equilibria, which are also temperature-dependent steps (discussed elsewhere).
The equilibrium constants K and K of Scheme 1 were determined from the
1
2
-
slopes and intercepts of the plots (Figs. 3, 4) of 1/kobs versus 1/[MOX] and 1/[OH ]
for different temperatures (Table 6). From the van’t Hoff plot, the thermodynamic
parameters, DH, DS, and DG for the formation of monohydroxo permanganate, and
complex between Mn(VII) and MOX anion were determined (Table 7).
Polymerization study
The intervention of free radicals in the reaction was examined as follows; the
reaction mixture containing Mn(VII) and MOX with the concentration of
-
.002 mol dm each at constant concentrations of OH and ionic strength in
3
-
0
which a known quantity of acrylonitrile scavenger has been initially added, was kept
for 1 h. On dilution with methanol, a copious precipitation resulted. This indicates
1
/D x 102
1
.25
1.35
1.45
1.55
1.65
1
1
1
1
1
1
1
.72
.67
.62
.57
.52
.47
.42
1
1
1
1
1
1
1
.70
.68
.66
.64
.62
.60
.58
1.37
0
.04
0.06
0.08
0.10
0.12
0.14
√I
Fig. 2 Effect of ionic strength (I) and dielectric constant (D) on oxidation of moxifloxacin by
permanganate in aqueous alkaline medium at 303 K
123

S. S. Badi, S. M. Tuwar
Table 4 Effect of temperature on the oxidation of moxifloxacin by permanganate in aqueous alkaline
medium
3
10 9 kobs (overall reaction)
Temperature (K)
a
b
Exptl.
Calc.
3
3
3
3
03
08
13
18
4.58
5.63
7.10
9.32
4.44
5.87
7.71
9.59
-
4
-4
] = 2.0 9 10 ; [MOX] = 2.0 9 10 ; [OH ] = 0.001; I = 0.007/mol dm
-3
-
-3
[MnO
a
Experimental
b
-2
-1
3
= 77.2 dm mol
-1
Calculated:
= 13.1 9 10 dm mol at 303 K in rate Eq. (11)
k
obs were calculated by using, k = 2.8 9 10
3
s
,
K
1
and
2
-1
K
2
that the reaction was routed through a free radical path. The experiment of either
Mn(VII) or MOX with acrylonitrile alone did not induce polymerization under
similar condition, as those induced with reaction mixture. It is also ascertained by
the decrease in rate with initial addition of monomer.
The permanganate in alkaline medium exhibits various oxidation states, such as
Mn(VII), Mn(V), and Mn(VI). During this study, the color of the solution changed
from violet to blue and then to green. The spectrum of green solution was identical
2
-
-
to that of MnO4 . The concentration of MnO4 decreases at 526 nm and increases
at 608 and 432 nm due to Mn(VI) which is one of the reduction products. No
3
-
evidence of hypomanganate, MnO4 with maxima located at 667 nm was seen in
the present study. However, the reaction mixture turned to brown turbidity after
keeping for 1 h, and development of pale yellow due to another oxidative product.
This indicates that the manganate thus formed disproportionate to form perman-
ganate and manganese dioxide as shown below:
2
ꢁ
ꢁ
ꢁ
3
MnO4 þ 2H2O ! 2MnO þ MnO2 þ OH
ð2Þ
4
-
Potassium permanganate in alkali medium existed as MnO
and [MnO (-
4
4
2
OH)] , respectively, as given below:
-
K
1
ꢁ
ꢁ
2ꢁ
MnO þ OH ꢀ ½MnO ðOHÞꢂ
ð3Þ
4
4
Table 5 Activation parameters
for the oxidation of
Activation parameters
Values (overall
reaction)
moxifloxacin by permanganate
in aqueous alkaline medium at
-
1
E
a
(kJ mol
=
)
-1
37.4 ± 1
34.9 ± 1
-166 ± 4
85 ± 2
303 K
DH (kJ mol
)
=
-1
-1
DS (J K mol
)
=
-1
DG (kJ mol
)
Log A
4.0 ± 0.1
1
23

Permanganate oxidative products of moxifloxacin
K1
MnO - + OH-
[MnO (OH)]
2-
(i)
4
4
OCH3
N
N
N
F
H
K2
2
-
+
[MnO (OH)]
Complex
4
COO-
(
ii)
O
.
k
OCH3
N
H
Complex
MnO42- + H O
+
N
N
2
slow
F
COO-
(
iii)
O
.
OCH3
+
N
OCH3
N
H
N
N
H
fast
N
F
N
O
[MnO (OH)]2
-
+
4
F
COO-
O
COO-
+
MnO 2- + OH-
4
(
iv)
+
O
OCH3
OCH3
N
N
N
F
N
O
N
F
N
H
fast
H
n
+
2nOH-
COO-
COO-
+
nH O + (n -1) other minor products
2
(v)
Scheme 1 Mechanism of oxidation of moxifloxacin by permanganate in alkali
3
Equilibrium constant, (K ) for the above step was reported to be as 70 dm mol
-1
1
[
concentration used, the MnO4 is almost existed as [MnO (OH)] , which is
52]. In the present study, under the experimental condition and the alkali
2-
-
4
3
evidenced by the K value (77.2 dm mol ). The reports of previous study of
-1
1
oxidation of ketorolac by permanganate in alkali supports the existence of
-
equilibrium between Mn(VII) and OH (68.7 dm mol ).
3
-1
-
The species of MnO4 in alkali depicted as [MnO (OH)] is acting as a single
2-
4
2
equivalent oxidant and it undergoes reduction up to manganate only (MnO ) as
-
4
-
the alkali concentration was maintained well below 0.01 mol dm . If its
3
-
concentration exceeds 0.1 mol dm , there was a possibility to undergo reduction
3
5
up to Mn and re-oxidation to Mn in a fast step as shown below:
?
6?
123

S. S. Badi, S. M. Tuwar
5
4
3
2
1
00
00
00
00
00
0
(
a)
b)
(
(
c)
d)
(
0
200
400
600
800
1000
1200
3
-1
1
/ [MOX] (dm mol )
1 2
Fig. 3 Verification of rate law (11) and for calculation of k, K and K for the mechanism of oxidation of
moxifloxacin by permanganate in aqueous alkaline medium at different temperatures (conditions as in
Table 2). Temperature: a 303 K, b 308 K, c 313 K, d 318 K
2
2
1
1
50
00
50
00
(
a)
(
b)
(
c)
(
d)
5
0
0
0
200
400
600
800
1000
-
3
-1
1
/ [OH ] (dm mol )
1 2
Fig. 4 Verification of rate law (11) and for calculation of k, K , and K for the mechanism of oxidation
of moxifloxacin by permanganate in aqueous alkaline medium at different temperatures (conditions as in
Table 3). Temperature: a 303 K, b 308 K, c 313 K, d 318 K
1
23

Permanganate oxidative products of moxifloxacin
Table 6 Rate constants and
Constants
Temperature (K)
equilibrium constants involved
in the mechanism of oxidation
of moxifloxacin by
3
03
308
313
318
permanganate in aqueous
alkaline medium at different
temperatures
2
k 9 10 (s
-1
)
-1
3.54
2.84
1.95
110
2.42
130
3
K
1
2
(dm mol
)
3
77.2
13.1
95.4
16.6
-
9 10 (dm mol
2
-1
K
)
23.0
32.0
Table 7 Thermodynamic parameters of various steps of mechanism of oxidation of moxifloxacin by
permanganate in aqueous alkaline medium at 303 K
-1
-1
-1
-1
Equilibrium step
DH (kJ mol
)
DS (J K mol
)
DG (kJ mol
)
1
.
.
28.0 ± 1
48.1 ± 1
129 ± 2
219 ± 3
-11.0 ± 1
2
-18.1 ± 0.5
7
þ
ꢁ
5þ
Mn þ 2e ! Mn
ð4Þ
ð5Þ
Mn þ Mn7þ ! Mn6þ
5
þ
-
Such a possibility is ruled out due to the low concentration of OH used.
-
-
-
When MnO4 is a single equivalent oxidant at low [OH ], the hydride ion (H )
abstraction from the substrate is ruled out. It is possible [53] only when it is reduced
5
?
-
to hypomanganate (Mn ) by the abstraction of two electrons in the form of H .
Non-detection of peak at 667 nm due to hypomanganate and intervention of free
radicals from the polymerization study also rules out such a possibility.
-
-
Polymerization test with OH in MnO4 but in absence of MOX fails to yield the
precipitate. Nonetheless, the polymerization test was positive with MOX, even in
-
the absence of OH . Hence, such possibility of generation of free radical from the
-
OH may be ruled out. Thus, it may be concluded that the mechanism of oxidation
of MOX by permanganate in alkali follows as per the Scheme 1.
The reaction between permanganate and MOX in alkaline medium has a
stoichiometry of almost 2:1 for a major product, 1-cyclopropyl-6-fluoro-1,4-
dihydro-7-(octahydro-2-oxopyrrolo [3,4-b] pyridine-6-yl)-8-methoxy-4-oxoquino-
line-3-carboxylic acid, and a first-order dependency on the [Mn(VII)] and less than
unit order dependence on both the concentration of alkali and MOX. Since the
permanganate species is one electron oxidant in alkaline medium, a reaction
between substrate and oxidant would afford a free radical intermediate evidenced by
polymerization test. The initially added products had shown no effect on rate of
reaction. The results imply that first the alkali present in the reaction mixture
combines with permanganate ions to give a mono-hydroxo permanganate species,
2
-
[
[
MnO (OH)] in a prior equilibrium step (1), which is in accordance with literature
4
-
54], and also supported by experimentally observed order in [OH ]. In the next
2
-
equilibrium step, [MnO (OH)] formed immediately combines with MOX to form
4
an intermediate complex (2). The fractional order with respect to MOX presumably
123

S. S. Badi, S. M. Tuwar
B= m/z = 449.43
HOOC
HOHN
O
OCH3
OCH
3
OCH3
N
N
N
F
N
O
H N
N
O
H
2
N
F
COOH
F
COOH
COOH
O
C= m/z = 415.41
A= m/z = 292.26
OCH3
N
H
N
N
O
MOX= m/z = 400.42
F
COO-
O
N
O
HO
O-OC
F
OCH3
N
Mn
N
F
N
O
O
N
H
N
OH
O
OCH3
COO-
O
Mn
O
D= m/z = 534.35
E= m/z = 478.29
HO
O
O
O
HOOC
F
F
COOH
O
O
N
N
OCH3
N
N
OCH3
Mn
N
N
O
O
F= m/z = 917.24
Scheme 2 Oxidative products of moxifloxacin as per LC–ESI–MS Spectra. [A] 7-amino-1-cyclopropyl-
-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3- carboxylic acid. [B] 7-(3-(2-carboxyethyl)-4-
6
hydroxylamine-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic
acid. [C] 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(octahydro-2-oxopyrrolo[3,4-b]pyridin-6-yl)-8-methoxy-4-
oxoquinoline-3-carboxylic acid. [D] 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(octahydro-2-oxopyrrolo
[
4
3,4-b]pyridin-6-yl)-8-methoxy-4-oxoquinoline-3-carboxylic acid permanganate complex. [E] 7-(3-amino-
-hydroxypyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid
permanganate complex. [F] Di-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(octahydro-2-oxopyrrolo[3,4-
b]pyridin-6-yl)-8-methoxy-4-oxoquinoline-3-carboxylic acid permanganate complex
resulted from the complex formation between oxidant and substrate prior to the slow
step. However, the evidence for complex formation is obtained by kinetic studies,
i.e., from the Michaelis–Menton plot (1/kobs versus 1/[MOX]). Further, the
intermediate complex decomposes in a slow step (3) to form a free radical derived
from MOX. Thus, the free radical formed reacts with another molecule of
2
-
[
pyl-6-fluoro-1,4-dihydro-7-(octahydro-2-oxopyrrolo[3,4-b]pyridin-6-yl)-8-methoxy-
MnO (OH)] in subsequent fast steps (4 and 5) to yield the product 1-cyclopro-
4
4
-oxoquinoline-3-carboxylic acid, and other products as in Schemes 1 and 2.
The multiple m/z values of ESI–MS spectra prove the existence of different
products (A, B, C, D, E, and F), resulted due to oxidation. Such values can be
1
23

Permanganate oxidative products of moxifloxacin
assigned to the different possible products of MOX are as shown in Scheme 2. The
oxidative products obtained (A, B, and C) from MOX in the present study are
similar to the oxidative products of other FQs [42] and also the products of
photochemical decomposition of MOX [44]. However, the abnormal high values of
m/z can be assigned to the permanganate complexes of the products (D, E, and F),
which are unusual in the non-metallic [42] oxidation of MOX. Nevertheless, the
literature reveals that there is evidence for the formation of complex between Fe(III)
and MOX [46]. Hence, formation of such complexes cannot be ruled out.
The rate law for the Scheme 1 can be derived as follows:
ꢁ
d½MnO ꢂ
4
Rate ¼ ꢁ
¼ k½Complexꢂ
dt
2ꢁ
ð6Þ
Rate ¼ kK ½MnO ðOHÞꢂ ½MOXꢂ
2
4
f
ꢁ
ꢁ
f
Rate ¼ kK1K2½MnO ꢂ ½OH ꢂ ½MOXꢂ
4
f
f
However,
ꢁ
ꢁ
2ꢁ
½
MnO ꢂ ¼ ½MnO ꢂ þ ½MnO ðOHÞꢂ þ ½Complexꢂ
4
T
4
f
4
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
f
¼
¼
½MnO ꢂ þ K1½MnO ꢂ ½OH ꢂ þ K1K2½MnO ꢂ ½OH ꢂ ½MOXꢂ
½MnO ꢂ f1 þ K ½OH ꢂ þ K K ½MOXꢂ ½OH ꢂ g
4
f
4
f
f
4
f
f
ꢁ
ꢁ
ꢁ
4
f
1
f
1
2
f
f
ꢁ
½
MnO ꢂ
ꢁ
4
T
½
MnO ꢂ ¼
4
f
ꢁ
ꢁ
f
1
þ K1½OH ꢂ þ K1K2½MOXꢂ ½OH ꢂ
f
f
ꢁ
ꢁ
2ꢁ
½
OH ꢂ ¼ ½OH ꢂ þ ½½MnO ðOHÞꢂ
ꢂ
T
f
4
ꢁ
ꢁ
ꢁ
¼
¼
½OH ꢂ þ K1½MnO ꢂ ½OH ꢂ
ð7Þ
ð8Þ
f
4
f
f
ꢁ
ꢁ
½OH ꢂ f1 þ K ½MnO ꢂ g
f
1
4
f
ꢁ
½OH ꢂ
ꢁ
T
½
OH ꢂ ¼
f
ꢁ
1
þ K1½MnO ꢂ
4
f
-
-
At low concentration of [Mn(VII)], [OH ] = [OH ]
f
T
½
MOXꢂ ¼ ½MOXꢂ þ ½Complexꢂ
T
f
ꢁ
ꢁ
¼
¼
½MOXꢂ þ K1K2½MnO ꢂ ½OH ꢂ ½MOXꢂ
f
4
f
f
f
ꢁ
ꢁ
½MOXꢂ f1 þ K K ½OH ꢂ ½MnO ꢂ g
f
1
2
f
4
f
½
MOXꢂ
½
MOXꢂ ¼ 1
f
ꢁ
ꢁ
4
f
þ K1K2½OH ꢂ ½MnO ꢂ
f
-
The term K K [OH ] [MnO ] can be neglected compared to 1 in the denominator
-
1
2
f
4
f
-
as low concentration of MnO4 used. Therefore,
½
MOXꢂ ¼ ½MOXꢂ
ð9Þ
f
T
On substituting Eqs. (7), (8), and (9) in Eqs. (6), (10) results.
123

S. S. Badi, S. M. Tuwar
ꢁ
ꢁ
T
kK1K2½MnO ꢂ ½OH ꢂ ½MOXꢂ
4
T
T
Rate ¼ 1
ð10Þ
ꢁ
ꢁ
f
þ K1½OH ꢂ þ K1K2½MOXꢂ ½OH ꢂ
f
f
For verification of rate law, the subscripts ‘T’ and ‘f’ are omitted and hence Eq. (10)
becomes Eq. (11) is rearranged into Eq. (12)
ꢁ
Rate
kK1K2½OH ꢂ½MOXꢂ
¼
kobs ¼
ð11Þ
ꢁ
ꢁ
ꢁ
½
MnO ꢂ
1 þ K1½OH ꢂ þ K1K2½MOXꢂ½OH ꢂ
4
1
1
1
1
¼
þ
þ k
ð12Þ
ꢁ
kobs
kK1K2½OH ꢂ½MOXꢂ kK2½MOXꢂ
Rate law (11) can be rearranged in the form of Eq. (12) and is verified by plotting of
-
1
/kobs versus 1/[OH ] and 1/[MOX] for all of which should be linear and are found
so in Figs. 3, 4, and 5. From the slopes and intercepts of these plots, the values
-
2
-1
3
-1
2
3
-1
k = 2.8 9 10 s , K = 77.2 dm mol , and K = 13.1 9 10 dm mol for
03 K are calculated. The value of K obtained in this study is in close agreement
1
2
3
1
3
-1
with the literature [52] value (70 dm mol ). Further, these values are used in rate
law (11) at different experimental conditions to regenerate kobs. The regenerated
values are found to be in close agreement with those of experimental values
(Table 1). This fortifies the mechanism of oxidation as shown in Scheme 1 and rate
law (11).
The thermodynamic quantities for the equilibrium steps in Scheme 1 (Table 7)
-
can be evaluated as follows; the [OH ] and [MOX] were varied at four different
temperatures and k, K , and K values were determined (Figs. 3, 4) at each
1
2
-
3
-1
1
/ [OH ] (dm mol )
0
200
400
600
800
1000
1200
3
00
50
4
3
2
1
00
00
00
00
0
2
200
1
1
5
0
50
00
0
0
250
500
1
750
1000
-1
1250
1500
3
/ [MOX] (dm mol )
Fig. 5 Verification of rate law (11) for the oxidation of MOX by permanganate in aqueous alkaline
medium for 303 K (conditions as in Table 1)
1
23

Permanganate oxidative products of moxifloxacin
temperature (Table 6). The K and K values are found to be increased with increase
1
2
in temperature. The van’t Hoffs plots were made for the variation of K and K with
1
2
temperature and the enthalpy of reaction (DH) was evaluated from its slope. The
free energy change (DG) of the reaction was calculated from the relation between
DG and equilibrium constant K ; using DH and DG, the value of DS was
1
determined. Similarly, DH, DS, and DG were calculated for K for the equilibrium
2
(
2) (Table 7). The oxidation presumed to be occurred through a bridging nitrogen
atom of piperazine ring. Thus, the inner sphere mechanism of oxidation of MOX by
permanganate is expected. This is evidenced by the small value of frequency factor
-
1
=
-1
-1
(
4.0), activation energy 37.4 kJ mol , and DS (-166 J K mol ). Further, the
=
-1 -1
large negative value of DS (-166 J K mol ) indicates that the activated
complex thus formed is more ordered than its reactants.
Since moxifloxacin has both COOH and NH2 groups, it is an amphoteric
molecule [55] having pKa of 6.25 and pKa of 9.29. At pH above or below of its
1
2
isoelectric point (pH 8.0), the molecule will be charged, while at its isoelectric point
it will be devoid of charge. Hence, the alkali maintained in the present study reveals
that MOX may be existed in amphoteric form. The negative end of Mn(VII) through
oxygen may be interacted with positive end of MOX at nitrogen of piperazine
moiety. The interaction of these opposite charges might have been decreased in the
rate of reaction with increase in ionic strength (-1.0). The study of variation of
dielectric constant of the medium with different percentage composition of t-butyl
alcohol and water on rate of reaction reveals that the rate increases with an increase
in dielectric constant of the medium. It can be concluded that the activated complex
may be more solvated at higher dielectric constant medium, supported by a negative
slope in the plot of log kobs versus 1/D (Fig. 2). Further, this activated complex may
=
be more rigid than the reactants, evidenced by large negative value of DS
-
1
-1
=
-1
(
-166 J K mol ) and large positive value of DG (85 kJ mol ).
The DH and DS values of equilibria (1) and (2) indicate that the formation of
monohydroxo permanganate species and the formation of complex between oxidant
and reductant are endothermic processes and formed by gain of degrees of freedom.
Thus, such complexes may be highly reactive, evidenced by a large value of ‘k’
-
2 -1
(
reveal the formation of monohydroxo permanganate species and complex are
2.8 9 10
s ). The negative DG (Table 7) values for both the steps, (1) and (2),
thermodynamically governed.
Conclusions
Kinetics of oxidation of MOX by Mn(VII) in alkali was followed by the
intervention of free radical generated from MOX. The LC–ESI–MS studies reveal
that there will be more than one oxidative product. Some major oxidative products
are identified. Out of which three are of usual products, similar to FQs oxidations
and the remaining are permanganate complexes. The main product was identified as
1
6
-cyclopropyl -6-fluoro -1,4- dihydro -7- (octahydro -2- oxopyrrolo [3,4-b] pyridin -
-yl)-8-methoxy-4-oxoquinoline-3-carboxylic acid. The proposed mechanism
involves multiple equilibria. The equilibrium constants are evaluated and compared
123

S. S. Badi, S. M. Tuwar
with the equilibrium constants of previous studies. The small value of log A
indicated that the electron transfer takes place through inner-sphere mechanism. The
2
thermodynamic parameters suggest that [MnO (OH)] and intermediate complex
-
4
are thermodynamically governed.
Acknowledgments The authors are grateful to the Principal, Karnatak Science College, Dharwad,
Karnataka, India for providing the necessary facilities to carry out this work. They also thank the
Raptakos Brett and Co., Microlabs Ltd. KLAB, Mumbai, India for providing the free sample of
Moxifloxacin.
References
1
2
3
4
5
6
7
. A. Carrington, M.C.R. Symons, Chem. Rev. 63, 443 (1963)
. M. Jaky, L.I. Simandi, J. Chem. Soc. Perkin Trans. 2, 939 (1976)
. P. Nath, K.K. Banerji, Indian J. Chem. 14, 660 (1976)
. M. Jaky, J. Szammer, E. Simon-Trompler, J. Chem. Soc. Perkin Trans. 2, 1597 (2000)
. P.K. Sen, P.R. Samaddar, K. Das, Transit. Met. Chem. 30, 907 (2005)
. K. Mohnot, P.K. Sharma, K.K. Banerji, J. Org. Chem. 61, 1310 (1996)
. S.A. Khan, P. Kumar, K. Saleem, Z. Khan, Colloids Surf. A: Physicochem. Eng. Asp. 302, 102
(2007)
8. E. Block, R. DeOrazio, M. Thiruvazhi, J. Org. Chem. 59, 2273 (1994)
9. N. Xie, R.A. Binstead, E. Block, W.D. Chandler, D.G. Lee, T.J. Meyer, M. Thiruvazhi, J. Org. Chem.
65, 1008 (2000)
1
1
1
1
1
0. A.R. Hajipour, S.E. Mallakpour, H. Adibi, Sulfur Lett. 25, 155 (2002)
1. P. Kumar, Z. Khan, Colloid Polym. Sci. 284, 1155 (2006)
2. N.N. Halligudi, S.M. Desai, S.T. Nandibewoor, Transit. Met. Chem. 26, 28 (2001)
3. R.G. Panari, R.B. Chougale, S.T. Nandibewoor, Polish J. Chem. 72, 99 (1998)
4. P.B. Addis, A.S. Csallany, S.E. Kindom, Some lipid oxidation products as xenobiotics, in Xenobi-
otics in Foods and Feeds, ed. by J.W. Finley, D.E. Schwass (American Chemical Society, Wash-
ington, DC, 1983), p. 85
1
1
1
1
1
5. J.R. Hanson, P.B. Hitchcock, S.J. Nagaratnam, J. Chem. Res. Synop. 22 (1999)
6. S. Dash, S. Patel, B.K. Mishra, Tetrahedron 65, 707 (2009)
7. L.I. Simandi, M. Jaky, Z.A. Schelley, J. Am. Chem. Soc. 107, 4220 (1985)
8. P.L. Timmanagoudar, G.A. Hiremath, S.T. Nandibewoor, Transit. Met. Chem. 22, 193 (1997)
9. U.S. Environmental Protection Agency. In Situ Remediation Technology: In Situ Chemical Oxidation
EPA542-R-98-008; Office of Solid Waste and Emergency Response (U.S. EPA, Washington, DC,
1998)
2
0. R.L. Siegrist, M.A. Urynowicz, O.R. West, M.L. Crimi, K.S. Lowe, Principles and Practices of
In Situ Chemical Oxidation Using Permanganate (Battelle, Columbus, OH, 2001)
1. Y. Eugeneyan, F.W. Schwartz, Environ. Sci. Technol. 34, 2535 (2000)
2
2
2. V.T. Andriole, The quinolones: Prospects, in The quinolones, 3rd edn., ed. by V.T. Andriole
(
Academic Press, London, 2000), p. 487
3. J.O. Maryadele, The Merck Index: An Encyclopedia of Chemicals, Drugs and Biologicals, 14th ed.
Merck Research Laboratories, Division of Merck and Co., Inc. Whitehouse Station, New Jersey,
001), pp. 1125
4. British Pharmacopoeia, The Stationary Office Medicinal, Pharmaceutical Substances, London 2,
401 (2009)
2
(
2
2
1
2
2
2
2
5. V.T. Andriole, Clin. Infect. Dis. 41, 113 (2005)
6. J.J. Champoux, Annu. Rev. Biochem. 70, 369 (2001)
7. USP DI., Vol. I, 21st edn. (Micromedex, New York, NY, 2001), pp. 1528
8. E. Miyazaki, M. Miyazaki, J.M. Chen, R.E. Chaisson, W.R. Bishai, Moxifloxacin (BAY12-8039).
Antimicrob. Agents Chemother. 43, 85 (1999)
29. U. Hubicka, B. Zuromska-witek, J. Krzek, M. Walczak, M. Zylewski, Acta Poloniae Pharmaceut.
Drug Res. 69, 821 (2012)
30. E.M. Golet, A.C. Alder, W. Giger, Environ. Sci. Technol. 36, 3645 (2002)
1
23

Permanganate oxidative products of moxifloxacin
3
1. D.W. Kolpin, M. Skopec, M.T. Meyer, E.T. Furlong, S.D. Zaugg, Sci. Total Environ. 328, 119 (2004)
2. D.W. Kolpin, E.T. Furlong, M.T. Meyer, E.M. Thurman, S.D. Zaugg, L.B. Barber, H.T. Buxton,
Environ. Sci. Technol. 36, 1202 (2002)
3
33. N.M. Vieno, H. Harkki, T. Tuhkanen, L. Kronberg, Environ. Sci. Technol. 41, 5077 (2007)
34. W. Xu, G. Zhang, X. Li, S. Zou, P. Li, Z. Hu, J. Li, Water Res. 41, 4526 (2007)
35. F. Tamtam, F. Mercier, B. Le Bot, J. Eurin, Q.T. Dinh, M. Clement, M. Chevreuil, Sci. Total
Environ. 393, 84 (2008)
36. J.E. Renew, C.H. Huang, J. Chromatogr. A 1042, 113 (2004)
37. H. Nakata, K. Kannan, P.D. Jones, J.P. Giesy, Chemosphere 58, 759 (2005)
38. S. Castiglioni, R. Bagnati, R. Fanelli, F. Pomati, D. Calamari, E. Zuccato, Environ. Sci. Technol. 40,
357 (2006)
3
4
4
9. K.G. Karthikeyan, M.T. Meyer, Sci. Total Environ. 361, 196 (2006)
0. M. Seifrtova, A. Pena, C.M. Lino, P. Solich, Anal. Bioanal. Chem. 391, 799 (2008)
1. B. Wiedemann, H. Grimm, Susceptibility to antibiotics: species incidence and trends. in Antibiotics
in Laboratory Medicine, ed. by V. Lorian (Williams and Wilkins, Baltimore, MD, 1996), pp. 900
2. P. Wang, H. Yi-Liang, Ching-Hua, Water Res. 44, 5989 (2010)
4
4
3. H. Zhang, C.H. Huang, The 3rd International Conference on Pharmaceuticals and Endocrine Dis-
rupting Chemicals in Water (National Ground Water Association, Minneapolis, MN, 2003), pp. 19
4. H. Urszula, J. Krzek, B. Zuromska, M. Walczak, M. Zylewski, D. Pawlowski, Photochem. Photobiol.
Sci. 11, 351 (2012)
4
4
5. R.E.L. Sheikh, A.S. Amin, A.A. Gouda, A.G. Youssef, Pharm. Anal. Acta. 240, 2153 (2013). doi:10.
4172/2153-2435.1000240
4
4
4
6. W.F. El-Hawary, Kh Faisal, Al-Gethami. Eur. Chem. Bull. 2, 22 (2013)
7. A.I. Vogel, A text book of quantitative inorganic analysis, 4th edn. (ELBS, New York, 1978), p. 330
8. G.H. Jeffery, J. Bassett, J. Mendham, R.C. Denney, Vogel’s Text Book of Quantitative Chemical
Analysis, 5th ed. (ELBS, Longman, Essex, 1996), pp. 371
4
5
5
5
5
5
5
9. R.G. Panari, R.B. Chougale, S.T. Nandibewoor, Oxidn. Commun. 21, 503 (1998)
0. D.C. Bilehal, R.M. Kulkarni, S.T. Nandibewoor, Can. J. Chem. 79, 1926 (2001)
1. G.H. Hugar, S.T. Nandibewoor, Transit. Met. Chem. 19, 215 (1994)
2. P. Naik, S.A. Chimatadar, S.T. Nandibewoor, Ind. Eng. Chem. Res. 48, 2548 (2009)
3. M. Jaky, I.V. Kozhevnikov, E. Hoft, Int. J. Chem. Kinet. 24, 1055 (1992)
4. K.A. Thabaj, S.D. Kulkarni, S.A. Chimatadar, S.T. Nandibewoor, Polyhedrone 26, 4877 (2007)
5. J. Sharma, D.K. Majumdar, Int. J. Pharm. Pharm. Sci. 4, 605 (2012)
123