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Stability Studies of Lysine Acetylsalicylate (Aspirin Derivative): Mechanisms

of Hydrolysis

Article  in  Open Journal of Physical Chemistry · January 2012

DOI: 10.4236/ojpc.2012.22011

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Open Journal of Physical Chemistry, 2012, 2, 81-87 81
http://dx.doi.org/10.4236/ojpc.2012.22011 Published Online May 2012 (http://www.SciRP.org/journal/ojpc)

Stability Studies of Lysine Acetylsalicylate

(Aspirin Derivative): Mechanisms of Hydrolysis
Oussama Kamal1*, Abdelaziz Benlyamani1, Farid Serdaoui1, Mohammed Riri1, Abdelmjid Cherif1,
Miloudi Hlaïbi1,2
1
Laboratoire d’Interface Matériaux d’Electrochimie et Chimie de l’Environnement (LIME), Université Hassan II Faculté des
Sciences Aïn Chock, Casablanca, Morocco
2
Laboratoire des Polymères, Biopolymères, Surfaces, UMR 6270 du CNRS, Faculté des Sciences, Université de Rouen,
Mont-Saint-Aignan, France
Email: *kamaloussama@hotmail.fr

Received December 20, 2011; revised February 6, 2012; accepted March 9, 2012

ABSTRACT
To control the stability of the lysine acetylsalicylate compound (LAS) in aqueous solution, some studies of the hy-
dronium ion-catalyzed, hydroxide ion-catalyzed, and spontaneous reactions of this active ingredient in water solutions
have been carried out. The pH-rate profile (log kobs = f(pH)), shows that the hydrolysis reaction of the LAS, is con-
ducted by a catalysis acid-base mechanism, with multiple reaction pathways. The rate constants, kH, kOH and k0 to the
reaction pathways catalyzed by H3O+, HO– ions and to the spontaneous reaction, for the hydrolysis reaction of the re-
agent LAS, were determined. The results show that the studied compound LAS is unstable in basic medium and the
hydrolysis reaction catalyzed by HO– ions is predominant.For a known acidity (pH  10), studies conducted for differ-
ent temperatures of the medium, clearly indicate, that the experimental rate constant kobs ,depends on the temperature
according to the Arrhenius equation. The activation parameters: activation energy (Ea), enthalpy (ΔH≠) and entropy
(ΔS≠), for the transition state were determined, The very negative value obtained for the activation parameter ΔS*, first
indicates that in the transition state there is gain in order, then this late state, resembles the products and that probably
for the mechanism of the LAS hydrolysis reaction catalyzed by HO– ions, the rate-determining step is a bimolecular
reaction. Finally from all these results, the mechanism for the reaction pathway catalyzed by HO– ions has been eluci-
dated.

Keywords: Lysine Acetylsalicylate; Hydronium Ions Hydroxide Catalyzed; Catalysis Acid-Base Mechanism; Multiple
Reaction Pathways; Activation Parameters

1. Introduction or HO–) [1-6].

Since Edwards has shown that the rate of hydrolysis of
The LAS compound is an active ingredient known to
aspirin is independent of pH between pH 4 and 8, the reac-
Aspegic. It is a molecule that is part of the family of
tion has been the subject of a number of studies, particu-
salicylates including aspirin, which represents one of the
larly by Garrett [1,3-5]. Edwards suggested that in this
most commonly, used drugs in the world. Aspegic is an
pH range, the hydrolysis reaction resulting from the at-
acetyl derivative of salicylic acid that is a white, crystal-
tack by a water molecule on the anion of aspirin
line, weakly acidic substance. Acetylsalicylic acid decom-
(Scheme 1), but several authors have pointed out that
poses rapidly in solutions of ammonium acetate or of the
this mechanism is not consistent with Edwards’ own
acetates, carbonates, citrates, phosphates or hydroxides
demonstration, showing that the hydrolysis reaction is
of the alkali metals. Acetylsalicylic acid is stable in dry
air, but gradually hydrolyses in contact with moisture to not catalyzed by acetate ion, a considerably more power-
acetic and salicylic acids. In solution with alkalis, the hy- ful nucleophile than water.
drolysis proceeds rapidly and the clear solutions formed They considered that the facts point rather to intramo-
may consist entirely of acetate and salicylate. The prin- lecular nucleophilic catalysis by the ionized carboxyl
cipal cause of the hydrolysis of this family of the salicylic group [7,8]. This mechanism has been set out in its most
acid acyl esters (e.g. aspirin), in aqueous solution about acceptable form by Bender (Scheme 1) [9]. This hypothe-
pH 3, is the attack of these substances by water ions (H3O+ sis was supported by the same authors [10], which showed
that a small amount of labelled oxygen from solvent H182 O
*
Corresponding author. appears in the salicylic acid produced. Only Garrett has

Copyright © 2012 SciRes. OJPC

82 O. KAMAL ET AL.

O O
2. Experimental Section
O O
slow Inorganic salts were of analytical grade, and were used
O O without further purification, as well used normadoses
O
1 2 solutions of HCl and NaOH were analytical grade. Water
O was further glass distilled before use. The LAS was ob-
tained commercially. Aqueous solutions of reagent LAS
of known concentrations 5 × 10–4 M and 10–3 M were
prepared, the desired pH values are determined by adding
O O the quantities: HCl (0.5 M) or NaOH (1 M), respectively
CO2 for acidic or basic mediums and these pH values are
- H2O O
measured with a Hanna 210 microprocessor pH-meter,
+
H + CH3CO2 +
OH O equipped with a combined glass electrode and calibrated
3 with commercial buffers (pH 4.00 and 7.00). These solu-
tions are maintained at fixed temperature 298 K, and
Scheme 1. Hydrolysis reaction of the LAS reagent.
small aliquots were withdrawn at known time intervals.
seriously questioned this mechanism. He found that the These samples were analyzed by standard Helios  UV-
addition of ethanol to the solvent increases the rate of visible spectrometer, using quartz cells of optical path
solvolysis, and that ethyl acetate is then a product [3-6]. length l = 1 cm. The absorption measurements have been
He ruled out the possibility that the rate increase is a performed at wavelength max = 300 nm. Indeed, the UV-
generalized solvent effect by showing that the addition of visible spectra of Figure 1, clearly show that the salicy-
dioxane has very little effect on the rate of hydrolysis of late ion formed by hydrolysis of the LAS, has a maxi-
aspirin. Garrett tried to explain his results by proposing a mum band of absorption at max = 300 nm, and at this
mechanism involving nucleophilic attack by ethanol on maximum wavelength, the reagent LAS has a negligible
the tetrahedral carbon atom of the intermediate (2) absorption.
(Scheme 1), but this explanation has not been generally The initial concentration denoted “a” of the reagent
accepted [9]. Nevertheless, the demonstration that the has always been very low (5, 10–4 M), so that all the
addition of ethanol increases the rate of solvolysis does spectrophotometric measurements were carried out under
suggest strongly that the question of the involvement of a conditions of pseudo-first-order, with higher concentra-
molecule of solvent in the transition state ought to be tions of reacting species (H3O+, H2O and HO–), com-
reopened. The work of Jencks and Gilchrist [11] shows pared to this initial concentration a. All experimental
clearly that ethanol and ethoxide ion are stronger nucleo- values of optical densities were measured by reference to
philes than water and hydroxide ion in reactions at the pure water.
carbonyl group, and a rate-determining step involving
attack by either species would explain Garrett’s results. 3. Results and Discussion
It has been recognized for many years that over a suf- 3.1. Identification of the Catalysis Type for the
ficiently wide pH range, three kinetically-distinguishable Hydrolysis Reaction
mechanisms for the hydrolysis of some compounds, such
as epoxides and derivatives of acetylsalicylic acid [12-15]. The hydrolysis reaction of this reagent derivative of aspirin,
The experimental rate expression for their hydrolysis is
given by the following equation:
kobs  kH  H    k0  kOH OH   (1)

where kH is the specific second-order rate constant for the

hydronium ion-catalyzed reaction, k0 is the specific
first-order rate constant for the spontaneous reaction, and
kOH is the specific second order rate constant for the hy-
droxide-catalyzed reaction. This paper reports on the hy-
drolysis kinetics of the LAS compound (LAS), for pH
values between 0.50 and 13. This detailed study for a
wide range of pH, allows the one hand, to extract sig-
nificant results and secondly, to have an overview on the
various possible mechanisms for the hydrolysis of this Figure 1. UV-Visible spectra for the hydrolysis of the reagent
important reagent. LAS, pH = 11.66, [LAS] = 5 × 10–4 M.

Copyright © 2012 SciRes. OJPC

 O. KAMAL ET AL. 83

has been studied at 298 K in the pH range of 0.50 to 13 on the reaction of hydrolysis reagent LAS, is given by
and the kinetics of this hydrolysis phenomenon have the expression:
proved sensitive to the medium acidity, therefore, there is
possibility of the existence of a catalysis phenomenon by
 
kobs  kH  H    k0  kOH OH   (4)

ionic species of water (H3O+ and HO–). Generally, the It is obvious to note that the kinetic law of pseudo
mechanism of hydrolysis may be conducted according to first-order Equation (3) can be easily connected to changes
the following Scheme 2. in optical densities as a function of time, especially, only
The rate constants of second-order kH and kOH, are as- the hydrolyzed product absorbs at the measurement
sociated with catalytic decomposition process, respec- wavelength (max = 300 nm). Indeed, if D0, Dt and D∞ are
tively, in acidic and basic environments. While the rate respectively the values of optical density at t = 0, at time
constant of first-order k0, is involved in the process of t and at the end of the reaction and if sal is the molar
hydrolysis under the effect of solvent molecules, how- extinction coefficient of salicylate ion, we can write the
ever, it must be noted that this constant k0 result of the following relations:
operation kH2 O  55.55 (water concentration), with kH2 O D 0  0 ; Dt   sal lx ; D   sal la (5)
is the rate constant of second-order corresponding to the where l is the optical path, a and x are the respective
process of hydrolysis by an elementary molecule of the concentrations of LAS reagent and hydrolyzed product.
water. From the kinetic law of Equation (3) and the preceding
If a is the initial concentration of the reagent LAS, and relations Equation (5), we can establish relationships that
x the concentration of salicylate ions, formed at time t, express the evolution of the optical density versus time t.
and for a fixed acidity of the medium, the rate equation  a   D 
on the hydrolysis reaction is given by the following ex- ln    ln    kobs t (6)
ax  D  Dt 
pression:
and we see immediately that the value of the apparent
dx
dt
 
 kH  H    k0  kOH OH    a  x  (1) rate constant kobs is obtained from the slope of the straight
lines
After separation of variables, we have the relation:
 D 
dx

 kH  H    k0  kOH OH   dt (2) ln    f t  (7)
d a  x  D  Dt 
The integration of this relationship allows obtaining The graphic in Figure 2 illustrates the good linearity
the following kinetic equation: of the observed experimental lines.
Several experiments on the hydrolysis reaction of the
 a 
ln 
ax
  

  kH  H   k0  kOH OH  t  kobs t (3) reagent LAS, were performed for pH values from 0.50 to
13, with HCl and NaOH as agents, respectively to deter-
The apparent rate constant of pseudo first-order kobs, mine the pH of the studied solutions. For these experi-
ments, the kinetic experimental lines Equation (6) were
O
plotted and the apparent rate constants kobs were calcu-
O NH2 lated for all studied solutions, from the slopes of obtained
OH
O NH3+
LAS O
O

kH[H+] kOH[OH-]
k0

O Lysine Salicylate NH2

OH
O NH3+
+ O
O
CH3CO2H

Scheme 2. Different reaction pathways proposed for the Figure 2. Kinetics for the hydrolysis reaction of LAS re-
hydrolysis reaction of LAS. agent, in different basic solutions at 298 K.

Copyright © 2012 SciRes. OJPC

84 O. KAMAL ET AL.

lines. Table 1 includes all results related to the pheno- Therefore, the apparent rate constant kobs, expression is
menon of hydrolysis of the LAS compound. composed of three terms and is identified with the Equa-
These results show, firstly that the rate of hydrolysis tion (4). The shape of this curve on the pH-rate profile
reaction of this compound depends on the acidity of the clearly indicates that the hydrolysis reaction of the re-
medium and the reaction pathway catalyzed by the HO– agent LAS, is using three different reaction pathways, for
ions on the hydrolysis reaction is predominant, on the three different pH ranges and therefore, this reaction
other hand, values of these apparent rate constants (kobs) presents a phenomenon of acid-base catalysis. For pH
change in different ways, according to three pH ranges. values below 2, the curve has a negative slope (–1) and
From these values, the pH-rate profile graph (log kobs = in kobs expression Equation (4), the term kH is dominant,
f(pH)), was established (Figure 3), and the obtained ex- and this hydrolysis reaction proceeds according to the
perimental curve shows three different slopes (p = –1, 0 reaction pathway catalyzed by H3O+ ions. The zero slope
and +1). of this curve, presented for pH values between 2 and 8,
clearly indicates that in this pH range, the k0 term is pre-
Table 1. Evolution of the apparent rate constants (kobs) on dominant Equation (4), the apparent rate constant kobs
the medium acidity. depends on the concentration of HO– ions, and the hy-
pH Log (kobs)
drolysis process of LAS, results from the intervention of
these ions, according to the reaction pathway catalyzed
0.5 –3.222 by these ionic species HO–. From the curve in Figure 3,
0.7 –3.523 we determined the values of three rate constants kH, k0,
and kOH, for different reaction pathways that constitute
1.30 –3.886
the global mechanism for the hydrolysis process of the
3.00 –3.980 LAS reagent. Table 2 shows the values for these constants
4.00 –3.990 and the definitive expression of the apparent rate con-
5.30 –4.000 stant kobs at 298 K, is given by the following equation:
6.10 –4.097 kobs  1.73 103  H 3O    9.09 10 5 1.58 OH   (8)
7.04 –4.097
These results indicate that the hydrolysis reaction of
8.20 –4.000 the LAS reagent, is achieved using an acid-base catalysis
11.33 –2.602 mechanism, the reaction pathway catalyzed by HO– ions
11.95 –1.921
is dominant, and the degradation of this compound is
important in basic medium. This value of the rate con-
12.18 –1.726
stant kOH on the hydrolysis reaction of LAS in basic me-
12.37 –1.404 dium is the same order of magnitude as the values of the
12.50 –1.390 constants kOH determined for the picryl chloride and
trinitro-anisole hydrolysis reactions [16-18]. It is consid-
12.70 –1.211
erably less than the value calculated for the hydrolysis of
pH values determined by adding concentrated solutions of HCl and NaOH,
kobs in mn–1, [LAS] = 5 × 10–4 M. 7-chloro-4,6-dinitrobenzofurazan [19], while this value is
much higher than the values announced for the hydroly-
sis reactions of styrene oxides [20].

3.2. Determination of Activation Parameters and

Reaction Mechanism
To elucidate the temperature effect on the evolution of
the kinetic parameters relating to the reaction pathway
catalyzed by HO– ions, to determine the activation pa-
rameters, activation energy (Ea), enthalpy (ΔH≠) and en-
tropy (ΔS≠) for the transition state of the rate-determining
step and propose a mechanism for this predominant reac-

Table 2. The three rate constants for the hydrolysis phenome-

non of LAS.

kH (M–1·mn–1) k0 (mn–1) kOH (M–1·mn–1)

Figure 3. pH-rate profile for hydrolysis reaction of the LAS
reagent at 298 K. 1.73 × 10–3 9.09 × 10–5 1.58

Copyright © 2012 SciRes. OJPC

 O. KAMAL ET AL. 85

tion pathway in the hydrolysis process of studied reagent lar products and indicates that probably, for this reaction
(LAS). We followed the kinetics of the studied hydroly- pathway catalyzed by HO– ions, the intervention of the
sis reaction in basic medium of constant pH (10.12), by water molecule is in the rate-determining step, after the
varying the temperature between 298 and 323 K. The fast attack of the LAS reagent by very active HO– ion,
experimental values of the apparent rate constant kobs and that in the transition state there is a transfer of hy-
were calculated in the same way as the previous section, drogen atoms from one site to another. Indeed, some ki-
and Table 3 summarizes all results. netic studies [21,22] on hydrolysis reactions of some
The linear relationship between Ln kobs and the inverse organic compounds, have suggested mechanisms which
of absolute temperature (1/T) represented by the graph in involve a water molecule in the rate-determining step,
Figure 4, indicated firstly, that a consistent solvolysis and for this reaction pathway we propose the following
mechanism operated for this hydrolysis reaction pathway mechanism:
catalyzed by HO– ions, on the other hand, the Arrhenius
Table 3. The apparent rate constant kobs evolution vs. the
law is well verified for the studied temperatures and the
temperature.
activation parameters for this process were calculated
from the slope and intercept on the experimental right. 105.kobs (s–1 ) ln (kobs ) T (K) 103.1/T (K–1)
Ln kobs = f(1/T), plotted for the interval of studied
temperatures, with the following values for the activation 0.667 –11.917 298 3.36
energy Ea = (65.60  0.05) kJ.mol–1 and the preexponen- 1.160 –11.364 308 3.25
tial factor in the Arrhenius relationship A = (1.803 
2.830 –10.472 318 3.15
0.005) 106 s–1.
From these activation parameters, we determined at tem- 5.330 –9.840 323 3.09
perature T = 298 K, the magnitude of activation enthalpy pH = 10.12, [LAS] = 5 × 10–4 M, kobs in s–1.
ΔH≠ and entropy ΔS≠, according to the following expres-
sions derived from the theory of the transition state:
H   Ea  RT and S   R ln  A   30.46  (9)

After calculation we obtain the values:

H    63.12  0.05  kJ  mol1
S    133.42  0.05  J  K 1  mol 1
The ΔH≠ and ΔS≠ values associated with the solvolysis
phenomenon of LAS reagent, can propose a structure of
transition state on the studied reaction. In fact, a very
negative value for the activation entropy ΔS≠ reflecting a Figure 4. The Arrhenius representation Ln kobs = f(1/T) for
late transition state, very organized with a structure simi- the hydrolysis reaction of the LAS reagent at pH = 10.12.

O O

O Ly+ + OH- O Ly+

O O O O
R a p id p re -e q u ilib riu m
H
O

#
O O

O Ly+ + H 2O O Ly+

O O O O
S lo w s te p
H H H O
O O H
T ra n s itio n s ta te

O O
O O
O Ly+ - O Ly+
+ OH + OH O + H 2O
+
OH OH

Figure 5. Mechanism for hydroxide ion catalyzed hydrolysis of the LAS reagent.

Copyright © 2012 SciRes. OJPC

86 O. KAMAL ET AL.

This mechanism for the reaction pathway catalyzed by Society, Vol. 79, No. 13, 1957, pp. 3401-3408.
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[5] E. R. Garrett, “The Solvolysis of Aspirin Anhydride,” J
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