Oxidative degradation of paliperidone using potassium permangnate in acid medium

Article abstract of DOI:10.14233/ajchem.2019.21604

Oxidative degradation reactions of paliperidone are studied using potassium permanganate in acidic medium spectrophotometrically. Complete reaction was carried out in pseudo first order condition. The reaction orders were calculated with respect to the paliperidone and acid, the obtained values indicate that these reactant have less than first order dependency on the reaction rate. Oxidation products were identified using LC-MS technique and their m/z values were found to be 207, 221 and 443. Kinetics and the mechanism of the reactions were derived from the results identified. The reactions were studied at four different temperatures with different paliperidone and acid concentrations. The activation and thermodynamic parameters were calculated by graphical method.

Full text of DOI:10.14233/ajchem.2019.21604

Asian Journal of Chemistry; Vol. 31, No. 2 (2019), 389-392
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2019.21604
Oxidative Degradation of Paliperidone Using Potassium Permangnate in Acid Medium
1
1,*
1
2
3
1
4
S.S. KURDUR , K.A. THABAJ , R.M. KULKARNI , A.D. KULKARNI , D.P. RENDEDULA , S.A. MALLADI and P.B. BELAVI
1
2
Department of Chemistry, KLS Gogte Institute of Technology (Affiliated to Visvesvaraya Technological University), Belagavi-590008, India
Department of Applied Sciences, MIT Academy of Engineering (Affiliated to Savitribai Phule Pune University), Dehu Phata, Alandi (D),
Pune-412105, India
3
Department of Analytical Chemistry, GVK Biosciences Pvt. Ltd., Hyderabad-500076, India
Department of Physics, KLS Gogte Institute of Technology (Affiliated to Visvesvaraya Technological University), Belagavi-590008, India
4
*
Corresponding author: E-mail: atkiran@gmail.com
Received: 24 July 2018; Accepted: 12 October 2018;
Published online: 31 December 2018;
AJC-19214
Oxidative degradation reactions of paliperidone are studied using potassium permanganate in acidic medium spectrophotometrically.
Complete reaction was carried out in pseudo first order condition. The reaction orders were calculated with respect to the paliperidone and
acid, the obtained values indicate that these reactant have less than first order dependency on the reaction rate. Oxidation products were
identified using LC-MS technique and their m/z values were found to be 207, 221 and 443. Kinetics and the mechanism of the reactions
were derived from the results identified. The reactions were studied at four different temperatures with different paliperidone and acid
concentrations. The activation and thermodynamic parameters were calculated by graphical method.
Keywords: Kinetics, Paliperidone, Oxidative degradation, Mechanistic study.
INTRODUCTION
EXPERIMENTAL
Potassium permanganate is a well-known oxidizing agent
1] widely used in the in the oxidation reactions, synthetic as
The analytical grade chemicals are used throughout the
experiments. Deionized water is used for preparing all solutions.
The required proportion of a substance in a mixture of standard
potassium permanganate solution is obtained by dissolving
[
well as in the analytical methods [2]. The reaction medium
signifies the pathway of oxidation [3], as we know that perman-
ganate constitutes +2 to +7 states of manganese ion, among
weighed quantity of KMnO in deionized water. Similarly,
4
7+
these Mn is prominent oxidizing agent [4-6]. Similar study
of degradation of pharmaceutical drugs has been studied by
using different oxidant systems [7-10].
stock solution of paliperidone is prepared by using appropriate
amount of drug substance in 25 mL of 0.1N HCl and diluted
with deionized water to make it to 0.01M solution. The kinetic
measurements were carried out by using CARY 50 Bio make,
UV-Vis Spectrophotometer while the pH measurements were
performed on Elico make pH meter.
Procedure:The reaction kinetic and spectroscopic measure-
ments have been carried out at constant ionic strength by main-
taining pseudo first order conditions. Potassium permanganate
is used at least ten times less molar concentrations with respect
to paliperidone to maintain pseudo first order reaction condition.
9
-Hydroxyrisperidone (paliperidone, m.f. C23
H
27
N
4
O F,
3
molar mass 426.48 g/mol) is a drug which is a dopamine
antagonist and 5-HT2A antagonist. This drug is a charac-
teristic antipsychotic class of medicine [11-13]. It is used in
the treatment of mania and at lower doses as maintenances for
bipolar disorder and used also in the treatment of schizophrenia
and schizoaffective disorder [14]. Its bioavailability is 28 %
[
15]. This study has been undertaken as there was no degra-
dation study of paliperidone was carried out using any oxidi-
zing agents.
Paliperidone and KMnO
temperature and mixed together to initiate the reaction by keeping
4
solutions are maintained at constant
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390 Kurdur et al.
Asian J. Chem.
other reaction conditions constant. Constant temperature (25
0.1 ꢀC) is maintained throughout the experiment. The progress
of the reaction is monitored by measuring change in the absor-
bance of KMnO with respect to time. The chemical reaction
is carried out in a 1 cm quartz cell using UV-visible spectrophoto-
meter at 525 nm, λmax of KMnO . The Beer-Lambert law has
been verified for KMnO at absorption maximum 525 nm between
.0 × 10 to 1.0 × 10 by maintaining specified reaction conditions.
The molar absorbance coefficient calculated and is found to
TABLE-1
–
+
EFFECT OF VARIATION OF [MnO ], [PP] AND [H ] ON THE
4
±
OXIDATION OF PALIPERIDONE BY HMnO AT 25 °C
4
4
2
2
[
KMnO ] × 10
[PP] × 10
[HCl] × 10
-3
-1
4
4
-
3
-3
-3
kobs × 10 (s )
(mol dm )
(mol dm )
(mol dm )
5.00
5.00
5.00
5.00
5.00
5.00
5.00
5.00
5.00
5.00
5.00
5.00
0.06
0.08
0.10
0.50
2.00
3.00
5.00
0.50
1.00
2.00
3.00
3.00
3.00
3.00
3.00
3.00
0.40
0.70
1.00
2.00
3.00
4.00
3.00
3.00
3.00
3.00
3.00
3.00
3.00
2.6
2.4
2.6
2.7
2.5
2.4
0.4
0.7
0.9
1.8
2.5
2.8
1.3
1.5
1.7
2.1
2.4
2.6
2.7
4
4
-4
-3
1
2.50
3.00
3
-1
-1
4.00
3.00
3.00
3.00
3.00
3.00
as ε = 2357 dm mol cm . The graph between log [A
versus time is plotted and values are used in calculation of
pseudo first-order rate constants (kobs). Where A is the absor-
bance of unreacted KMnO at infinite time which does not include
Mn(VI) absorbance produced as one of the reaction product
and A is a absorbance of KMnO at any time ‘t’. The reaction
t
∞
− A ]
∞
4
t
4
3.00
3.00
is followed up to the three-fourth reaction completions. The
plots obtained over 75 % completions of reaction are linear.
The rate constants calculated are reproducible within the error
of ± 4 %.
3.00
3.00
3.00
3.00
3.00
3.00
RESULTS AND DISCUSSION
[
PP] = Paliperidone
Oxidation products of paliperidone: The LC-ESI-MS
is used for the analysis of reaction products in the solution form.
The LC-ESI-MS obtained indicate the presence of three major
products. The identified molecular ions have m/z values as
the reaction is observed at fixed concentrations of KMnO and
4
at a fixed ionic strength. It is found that kobs values increased
as the concentration of paliperidone is increased. This shows
the dependency of the reaction on paliperidone concentration.
The slope obtained from the plot of log kobs vs. log [paliperidone]
is 0.87 indicating less than first order dependence of paliperidone
concentration on the rate of reaction.
2
07, 221 443 and 427, where m/z 427 is a molecular ion of
paliperidone. The m/z 207, 221 and 443 are shown in the
Scheme-I. These identified products with above said m/z values
were also found earlier as oxidation reaction products [16] and
stress degradation products of paliperidone [17].
Reaction orders: The plots of log kobs versus log (conc.)
Variation of [acid]: The acid concentration varied from
-3
-3
-2
-3
are used to determine the orders of KMnO
4
, paliperidone and
4 × 10 mol dm to 1 × 10 mol dm at constant concentrations
of paliperidone and KMnO at 25 ꢀC (Table-1).The variation
acid. The concentrations of oxidant, reductant and hydrochloric
acid varied by maintaining other reaction conditions constant
to determine the orders of the each variant. Spectral behaviour
4
of acid does showed less effect on the reaction rate. The order
of the acid concentration is calculate and found as 0.16.
Effect of change in dielectric constant and ionic strength:
The dielectric constant of reaction mixture is changed by chan-
ging the volume ratio of t-butanol in water by keeping reaction
conditions constant. The t-butanol did not react with perman-
ganate in the present reaction conditions. The graph of log kobs
versus concentration of t-butanol (r > 0.983) was linear and
the rate constant kobs decreases with decrease in the polarity of
the reaction mixture. Ionic strength of the reaction mixture is
during oxidation of paliperidone by KMnO at 25 ꢀC is observed.
4
Variation of [oxidant]: Keeping paliperidone concen-
tration and ionic strength of a reaction mixture constant,
-5
-3
the KMnO concentration varied from 3 × 10 mol dm to 3 ×
4
-4
-3
1
0 mol dm concentration. The values are represented in
Table-1, which shows that the order with respect to perman-
ganate is unity. The linear plots obtained by pseudo-first order
graph (figure not shown) showing constant rate constants at
differentpermanganate concentrations under these conditions
also verifies the unit order dependency of the permanganate.
Variation of [paliperidone]: Paliperidone concentration
varied by increasing [KMnO ] from 0.1 to 0.6 M. Quantifiable
4
change on rate constant is not observed with the variation of
ionic strength.
-
2
-3
-3
-
was changed in the range from 3 × 10 mol dm to 3 × 10
Effect of [manganate]: The effect of initially added MnO
4
,
-3
mol dm (Table-1). The effect of this variation on the rate of
one of the reaction products is studied by varying manganate
OH2
OH2
F
N
N
F
F
O
H
OH2
HMnO species
N
4
N
N
O
N
+
N
N
+
O
H2C
N
O N
O
m/z 427
m/z 221
O
N
m/ z 201
m/z 443
O
N
+
Other products
Scheme-I: Oxidation reaction products of paliperidone by KMnO in acid medium
4

Vol. 31, No. 2 (2019)
Oxidative Degradation of Paliperidone Using Potassium Permangnate in Acid Medium 391
-
5
-4
+
concentration from 3 × 10 to 3 × 10 at constant concen-
trations of permanganate did not shows any significant effect.
Variation of temperature: The permanganate-palipe-
ridone redox reaction is carried out at four dissimilar temper-
atures by changing the [paliperidone] and [acid] solution. Ionic
strength and other conditions in the reaction mixture are kept
constant during this temperature variation. During reaction,
the rate constant k observed is increased with increase in
temperature. 1/kobs vs. 1/[paliperidone] and 1/kobs vs. 1/[HCl]
plots are plotted at dissimilar temperature and slopes and inter-
cepts of these graphs are used to calculate rate constant k of
the slow step (Scheme-II). Thermodynamic parameters are eval-
uated for the different rate constants at different temperatures
by using the Arrhenius equation. The graph of log k vs. 1/T is
plotted and evaluated energy of activation. Activation para-
meters obtained are given in Table-2.
threshold value at higher concentrations of H ion indicated
that in the acid permanganate protonated form is more active
[19]. The equilibrium of the reaction is represented in eqn. 1:
–
+
–
MnO
4
+ H
[HMnO
4
]
(1)
Stoichiometry of the reaction follows 2:1 oxidant and subs-
trate ratio i.e. two molecules of permanganates are required
for the complete oxidation of one molecule of paliperidone in
the acidic medium. This shows pseudo unit order dependency
on oxidant and less than first order dependency on [paliperidone]
and [H ] of acid medium. The oxidation products found are
Mn(II), 5-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole with m/z
21 is formed by the loss of m/z 207 molecule from the m/z
25. It is confirmed by the fragment found at m/z 207. One
+
2
4
more fragment is found at m/z 443 indicating the formation of
−
+
N-oxide molecule. At first MnO
HMnO . Thus formed HMnO
4
reacts with H so as to form
4
4
reacts with paliperidone
forming complex these two are known to be fast step later
complex breaks and oxidation products are formed by the
oxidation reaction. In this reaction, the breaking of complex
considered as a slow and rate determining step and is explained
in the following mechanism.
K1
MnO4- + H+
HMnO4
K2
HMnO4 + PP
Complex (C)
Complex (C)
Products
Mechanism is proposed for the reaction and based on the
experimental study for the oxidation of paliperidone using
k
slow
KMnO
4
in acidic medium:
Scheme-II
−
4
−
d[MnO ]
−
4
+
Rate =
= kK K [MnO ][PP] [H ]
f
(2)
1
2
f
dt
] is
TABLE-2
−
4
Total [MnO
ACTIVATION AND THERMODYNAMIC PARAMETERS
FOR THE OXIDATION OF PALIPERIDONE USING
POTASSIUM PERMANGANATE IN ACID MEDIUM
WITH RESPECT TO SLOW STEP OF THE SCHEME
–
–
[
=
=
MnO
4
]
4
T
–
= [MnO
4
]
f
+ [HMnO ] + [complex]
4
–
+
–
+
[MnO
[MnO
]
]
f
+ K
(1+ K
1
[MnO
4
+
][H ] + K
1
+
K
2
[MnO
4
][H ][PP]
–
4
f
1
[H ] + K
MnO ]
4 T
1 2
K [H ][PP]
Effect of temperature
Activation parameters
Parameters Values
3
–1
−
Temp. (K)
10 k s
2.5
[
+
−
#
-1
[MnO ] =
4 f
2
2
3
3
93
98
03
13
Ea (kJ mol )
30.05 ± 1
24.7 ± 1
-398.3 ± 5
68.5 ± 5
+
(3)
(
1+ K [H ]) + K K [H ][PP]
#
-1
1 1 2
3.3
3.8
∆H (kJ mol )
#
-1
-1
where f stands for free and T stands for total.
∆S (J K mol )
+
#
-1
5.7
∆G (kJ mol )
Total [H ] is given as:
Equilibrium constants K and K at different temperatures
+
+
1
2
[H ] = [H ] + [HMNO ] + [Complex]
T
f
4
3
–1
–3
–1
Temp. (K)
K (dm mol )
1
K (dm mol )
2
−
4
when very low concentrations of [MnO
are used then,
] and [paliperidone]
293
298
303
313
2.2
2.8
2.9
4.9
1.9
2.6
2.7
4.5
+
+
[H ] = [H ]
T
f
(4)
Likewise,
Thermodynamic quantities using K and K values
1
2
Quantities
Using K values
Using K values
[PP]
T
= [PP]
f
(5)
1
2
-1
∆
H (kJ mol )
-2.51
221.64
-69.4
-2.51
184.96
-58.3
Substituting eqns. 3 and 5 in eqn. 2 we get:
-
1
∆
S (J K-1mol )
−
4
+
-1
kK K [MnO ][PP] [H ]
∆
G (kJ mol )
1
2
f
f
+
Rate =
+
(6)
(7)
1
+ K [H ] + K K [PP] [H ]
1 f 1 2 f f
The expected active oxidizing ions of KMnO
4
in acidic
. Out of
is the powerful species in
low pH medium and Mn(II) is found to be the most stable
+
+
4
Rate
kK K [PP] [H ]
1 2 f f
+
medium are HMnO
4
2
, H MnO
, HMnO
4
3
and Mn
O
2 7
kobs
=
−
+
−
[
MnO ]
1+ K [H ] + K K [PP] [H ]
1 f 1 2 f f
these permanganate ions, MnO
4
The eqn. 7 can be rearranged as given below and also verifies
and confirms obtained orders with respect to different variations.
−
4
oxidation reaction product of MnO
As order with respect to acid concentration is less than unity
in aqueous acid medium, HMnO from permanganate ion acts
as an active species [18]. HMnO is the most reactive and more
is below 7 pH solution.
1
1
1
1
k
4
=
+
+
+
(8)
kobs
kK K [PP] [H ] kK [PP]
1 2 f f 2 f
4
productive species of Mn(VII) in comparison with perman-
ganate ion [19]. The rate of reaction is supposed to reach a
Eqn. 8 indicates that at constant conditions, plots 1/kobs
vs. 1/[paliperidone] gives a straight line with positive slope

392 Kurdur et al.
Asian J. Chem.
and intercept values at four different temperatures. Similarly,
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of degradation products. These formed products are less harm-
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in the reaction are environmentally friendly hence can be used
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2
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CONFLICT OF INTEREST
The authors declare that there is no conflict of interests
regarding the publication of this article.