Intensification of paracetamol (acetaminophen) synthesis from hydroquinone using ultrasound

Article abstract of DOI:10.1016/j.ultsonch.2018.07.029

Paracetamol (acetaminophen) is one of the most frequently used analgesic and antipyretic drugs. This work deals with ultrasound assisted synthesis (UAS) of paracetamol from hydroquinone using ammonium acetate as an amidating agent. The optimization of various reaction and ultrasound parameters was performed to minimize the energy and time requirement. UAS of paracetamol was achieved at a lower temperature (60 °C) and the time (150 min) without formation of salt as a byproduct, making reaction green and inherently safer. On the other hand, the conventional process requires high reaction temperature (220 °C) and time (15 h). The quantification of the product was done by using high performance liquid chromatography (HPLC). Optimization of parameters revealed that the percent yield of 57.72% can be obtained in 150 min by performing the reaction in the ultrasound bath at 22 kHz frequency, 60 °C temperature, hydroquinone to ammonium acetate and acetic acid in a molar ratio of 1:6:5, 125 W power, 50% duty cycle and agitation speed of 300 RPM. Hence, ultrasound assisted synthesis can be considered as a process intensification tool for the synthesis of paracetamol and possibly other pharmaceutical compounds.

Full text of DOI:10.1016/j.ultsonch.2018.07.029

Accepted Manuscript
Intensification of paracetamol (acetaminophen) synthesis from hydroquinone
using ultrasound
Swapnil N. Mane, Sagar M. Gadalkar, Virendra K. Rathod
PII:
S1350-4177(18)30461-9
DOI:
https://doi.org/10.1016/j.ultsonch.2018.07.029
ULTSON 4246
Reference:
To appear in:
Ultrasonics Sonochemistry
Received Date:
Revised Date:
Accepted Date:
21 March 2018
4 July 2018
20 July 2018
Please cite this article as: S.N. Mane, S.M. Gadalkar, V.K. Rathod, Intensification of paracetamol (acetaminophen)
synthesis from hydroquinone using ultrasound, Ultrasonics Sonochemistry (2018), doi: https://doi.org/10.1016/
j.ultsonch.2018.07.029
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Intensification of paracetamol (acetaminophen) synthesis from hydroquinone using
ultrasound
Swapnil N. Mane, Sagar M. Gadalkar, Virendra K. Rathod*
Department of Chemical Engineering,
Institute of Chemical Technology,
Matunga, Mumbai-400019,
India.
*
Corresponding Authors: Email ID: vk.rathod@ictmumbai.edu.in, Phone: 91-22-33612020, Fax:
9
1-22-24145614
1

Abstract
Paracetamol (acetaminophen) is one of the most frequently used analgesic and antipyretic drugs.
This work deals with ultrasound assisted synthesis (UAS) of paracetamol from hydroquinone
using ammonium acetate as an amidating agent. The optimization of various reaction and
ultrasound parameters was performed to minimize the energy and time requirement. UAS of
paracetamol was achieved at a lower temperature (60°C) and the time (150 min) without
formation of salt as a byproduct, making reaction green and inherently safer. While the
conventional process requires high reaction temperature (220℃) and time (15h). The
quantification of the product was done by using high performance liquid chromatography.
Optimization of parameters revealed that the percent yield of 57.72% can be obtained in 150
minutes by performing the reaction in the ultrasound bath at 22 kHz frequency, 60°C
temperature, hydroquinone to ammonium acetate and acetic acid in a molar ratio of 1:6:5, 125W
power, 50% duty cycle and agitation speed of 300 RPM. Hence, ultrasound assisted synthesis
can be considered as a process intensification tool for the synthesis of paracetamol and possibly
other pharmaceutical compounds.
Keywords: Paracetamol; hydroquinone; process intensification; ultrasound; HPLC.
2

1
Introduction
N-acetyl-para-aminophenol (APAP), known as paracetamol or acetaminophen, belongs to N-
arylamide class and is an important drug used for the treatment of pain and fever. Paracetamol is
one of the utmost consumed drugs globally with a production of more than 100,000 tons per year
[
1]. Necessity of drug in this enormous amounts for pharmaceutical industry, substantiated with
commercial aspects concerning the economic competence, lead to the requirement of
manufacturing these compounds through substitute routes in order to attain high purity in short
periods of time and with the consumption of a minimum quantity of solvents. To achieve best
synthesis route, studies have been performed using different starting compound , such as p-nitro-
chlorobenzene, nitrobenzene [2,3], p-nitrophenol [4] and hydroquinone [1,5]. Among these,
hydroquinone method comprises direct acetylation without need of extra steps involved in other
routes. In 2014, Joncour et al., established this green approach involving direct amidation of
hydroquinone to obtain paracetamol with greater conversion [1] which eliminates the problems
associated with the earlier techniques such as, the extra step involved, unwanted ortho-
isomerization, generation of the sulfate salt etc. Although the route established by Joncour et al.
has several advantages, it also unveils some glitches such as, time consuming (15 h) and
requirement of high operating temperature (220°C). The use of ultrasound can be an
intensification tool to overcome these issues, which can intensify the process with respect to
lowering reaction time, temperature and possibly solvent requirement.
Nowadays, ultrasound is used successfully used as process intensification tool in the field of
extraction bioactive compounds [6,7], synthesis of nanoparticles and pharmaceutical molecules
[
8,9]. Ultrasound enhances the chemical reactivity in a liquid medium through the generation and
destruction of cavitation bubbles. The ultrasound wave propagates through the liquid medium in
3

subsequent compression and rarefaction cycles, when the rarefaction cycle dominates the
attractive forces of the liquid or molecules present in it result in the formation of cavities. When
these cavities collapse the energy for chemical and mechanical effect of ultrasound is produced
leading to the generation of very high local temperatures and pressures [10]. Although ultrasound
is used for synthesis of various organic products, it has not been tried for the synthesis of
paracetamol to the best of knowledge. UAS is considerably faster, cleaner and eco-friendly
comparable with classical organic synthesis. Thus, the study is focused to explore the application
of ultrasound for the synthesis of paracetamol in a solvent-free reaction condition.
2
Materials and methods
2
.1 Materials
Ammonium acetate AR grade, hydroquinone AR grade, glacial acetic acid, acetonitrile (HPLC
grade), ethyl acetate AR grade and n-hexane AR grade were purchased from Thomas Baker
(
Chemicals) Pvt Ltd, and used without further purification.
.1.1 Ultrasound assisted synthesis
Ultrasonic bath (model 6.5l, 200 H, dakshin, India) with the internal dimensions as 300 mm ×
50 mm × 150 mm was used. Three neck flat bottom glass reactor of 50 mL capacity equipped
2
1
with a mechanical stirrer was used for performing the reaction. The reactor was held in the bath
at a sufficient water level based on maximum cavitation intensity to carry out the reaction. The
position of the reactor in the ultrasonic bath was fixed according to the maximum efficiency of
ultrasonic irradiation [11]. During the experiment, hydroquinone 2.2 g (0.02 mol), ammonium
acetate 3.15 g (0.04 mol) and acetic acid 6.75 mL (0.1 mol) were added in a glass reactor. Then
the reactor was placed in ultrasound bath with stirring and ultrasound irradiation. The reaction
was carried out for 180 minute and samples were withdrawn at known time intervals to
4

determine the conversion. Various temperatures such as ultrasound power, molar ratio, duty
cycle, temperature and agitation speed were optimized. In order to study the energy efficiency of
the ultrasonic bath, calorimetric studies were performed. Amount of energy dissipated in the bulk
of liquid was calculated by measuring the rise in temperature of a fixed quantity of reaction
mixture in an ultrasonic bath for a given time. Power dissipation was calculated as per Sutkar et
al. (2010) [12]. The analysis and quantitation of the product was done using HPLC analysis of
crude reaction mixture.
2
2
.2 Analytical method
.2.1 High performance liquid chromatography (HPLC)
HPLC analysis of the crude reaction mixture was done using a JASCO (4000 series) system with
a manual injector, pump (PU-4180) and UV/VIS (UV-4070) detector. JASCO Finepak SIL C18
column (250 x 4.6 mm, particle size 0.5 m) was used as stationary phase with mobile phase
comprising mixture of water and acetonitrile in the ratio of 70:30 (isocratic elution), at flow rate
-1
of 1 mL.min and detection wavelength of 254 nm. The percent yields were calculated from
calibration curve obtained from different concentrations of standard paracetamol.
3
Results and discussion
3
.1 Effect of temperature on conversion yield of paracetamol
Experiments were carried out to investigate the effect of temperature (Fig. 1) ranging from 30°C
to 70°C by keeping other parameters constant including agitation speed of 300 rpm, molar ratio
of hydroquinone to ammonium acetate and acetic acid 1:2:5 respectively, ultrasound frequency
2
3
2 kHz, power 50 W and duty cycle 50%. It was observed that 13.97%, 14.96%, 27.33% and
2.51% yield was obtained at 30°C, 40°C, 50°C and 60°C respectively. But further increase in
5

temperature to 70°C, leads to decrease in the yield. The rate of reaction increases with an
increase in reaction temperature because vapor pressure of solvent and/or molecules plays an
important role in cavitation effect that further affects the rate of reaction [13,14]. As higher
temperatures favor nucleophilic substitution reaction, increase in yield was observed up to 60°C
[
1]. However, decrease in the yield can be related to decreased cavitation effect of ultrasound, as
at higher temperatures the cavitation effect of ultrasound decreases. First, as the reaction
temperature is increased, the vapor pressure of the system is also increased which leads to easier
bubble formation (due to the decrease of the cavitation threshold), however, the cavitation
bubbles formed contain more vapor. In general, the largest sono-chemical effects are seen at
lower temperatures when a majority of the bubble contents is gas. In certain reaction systems, an
optimum reaction temperature lead to more favorable results. In such systems, an increase in
temperature causes increase in the kinetic of reaction up to a point at which the cushioning effect
of the vapor in the bubble begins to dominate the system. When this occurs, the rate of the
reaction decreases upon further increase in the reaction temperature [15]. The rate may also
reach a plateau with temperature and then decrease as the temperature increases [16]. Therefore,
considering the highest yield obtained, the temperature of 60°C was considered as optimum.
The reaction mechanism for conversion of hydroquinone (HQ) to acetyl para aminophenol
(APAP) is illustrated in Fig. 2. The reaction of HQ with ammonium acetate was possibly
progressed through the formation of para-aminophenol (PAP) as an intermediate, which further
directly acetylated to APAP producing two water molecules as side product [1]. According to
Joncour et al., at high temperature, ammonium acetate could be first dehydrated to acetamide and
further reacted with HQ to form APAP, which indicated possible contribution of ultrasound as an
6

increase in localized temperature due to cavitation which was contributed in nucleophilic
substitution reaction
3
.2. Effect of irradiation power on conversion yield of paracetamol
In order to find out the optimum input power for this reaction, the experiments were carried out
at irradiation power of 50W, 75W, 100W, 125W and 150W, keeping all other parameters
constant, such as ultrasound frequency 22 kHz, temperature 60°C, agitation speed of 300 rpm,
molar ratio of hydroquinone to ammonium acetate and acetic acid 1:2:5 respectively, and duty
cycle 50%. Fig. 3 revealed that, a yield of 32.51% was obtained after 3 h with irradiation power
of 50W and subsequent increase in power to 75W, 100W & 125W resulted in increased yield of
3
5.27%, 37.61% & 42.32% respectively. The irradiation power of 125W was considered as
optimized power for proceeding experiments as further increase in power to 150 W did not show
significant (43.45%) increase in the yield. It was found that as the amount of power delivered to
the reaction mixture increases, the rate of the reaction increases to a maximum limit and then
decreases with a continued increase in power [17]. A relatively small amount of energy supplied
is often sufficient for the reaction to take place. If the energy is too low, the cavitation threshold
may not be reached or the yield may be very low. Above the cavitation threshold the only effect
of increase in power is to produce more bubbles, with each bubble having same cavitation energy
level. A possible explanation for the observed decrease in rate at high powers is the formation of
a dense cloud of cavitation bubbles which try to block the energy transmitted to the fluid. If a
more number of cavitation bubbles are created in the bulk of the liquid, they are responsible for
an absorption of the acoustic energy which lowers the effective yield of the reaction [13].
Calorimetric study has been carried out to evaluate the efficiency of ultrasonic bath. Different
factors such as solvent, surface tension, viscosity and overall vessel geometry affect the power
7

dissipation. Dissipated power was computed from the temperature rise of the reaction mixture
after specific time at 25 and 40 kHz frequency with varying irradiated power (50 to 150 W).
Practical dissipated power was found to be 40.5, 47.8, 60.2 and 63.4 W for following input
power of 50, 100, 125 and 150 W respectively. Increase in actual power dissipation from 125 to
1
50W was marginal i.e. 60.2 and 63.4 W respectively. Consequently, with an increase in power
input to 150W was not contributed to yield improvement (43.45%), as compared to yield
42.32%) at power 125W. Therefore, further experiments were carried with optimized 125W
power input.
.3.Effect of molar ratio on conversion yield of paracetamol
(
3
Effect of different molar ratios of hydroquinone to ammonium acetate and acetic acid prove to be
important in terms of reaction economics. In order to study the effect of molar ratio on
ultrasound assisted reaction, a series of reactions were carried out by varying the molar ratio of
hydroquinone to ammonium acetate and acetic acid. Firstly, experiments were focused on to
optimize the concentration of ammonium acetate as it leads to incorporation of acetamido
functionality. Thus, hydroquinone (HQ), ammonium acetate and acetic acid were taken in
different ratios, keeping all other parameters constant (temperature 60°C, agitation speed of 300
rpm, ultrasound frequency 22 kHz, power 125W, and duty cycle 50%). The molar ratios of 1:2:5,
1
5
:3:5, 1:4:5, 1:6:5, 1:8:5 and 1:10:5 gave percent yield of 42.32%, 43.12%, 43.19%, 57.72%,
7.24% and 51.28% respectively. Here, increasing the amount of ammonium acetate leads to
increase in percent yield as ammonium acetate acts as nucleophile and is efficient amidating
agent. Finally, the molar ratio of 1:6:5 was taken as optimum, as it can be seen in Fig. 4, that
there is no significant increase in percent yield beyond this ratio.
8

As acetic acid is essential for acetylation and it also act as catalyst [1]. Acetic acid was taken in
the ratios of 1:6:5, 1:6:6 and 1:6:8, which gave yield of 56.91%, 57.04% and 54.59%
respectively, at constant parameters, temperature 60°C, agitation speed of 300 rpm, ultrasound
frequency 22 kHz, power 125W, and duty cycle 50%. Consequently, the ratio of 1:6:5 was taken
as optimum as there was no significant increase in the yield.
3
.4. Effect of duty cycle on conversion yield of paracetamol
Duty cycle represents the actual exposure time of ultrasound irradiation to the reaction mass in
one cycle, which can be varied by changing the on/off time of ultrasound [15]. On time indicates
exposure of ultrasonic waves which leads to generation of cavitation and off time indicates
resting period with no exposure of ultrasonic waves where cavitation bubbles gets sufficient time
to enlarge and burst. Application duty cycle increases the time of cavitation action and ultimately
the conversion. In order to investigate the effect of duty cycle on proceedings of reaction,
reactions were performed at different duty cycles of 40%, 50%, 60%, 70% and 80%, keeping all
other parameters like temperature 60℃, agitation speed of 300 rpm, ultrasound frequency 22
kHz, ultrasound power 125W, and molar ratio 1:6:5 as constant. Fig. 5 depicts that an increase in
the duty cycle (on time) resulted into increase in corresponding percent yield. Therefore, duty
cycle of 50% was taken as optimum considering economic and sustainability point of view. It is
always recommended to operate the reaction at a lower duty cycle to reduce the possible damage
to reaction mass by continuous exposure of ultrasonic waves. Also, keeping the ultrasound ‘on’
for a long time can damage the transducers, thus using recent instruments with better quality
transducers should be preferred [18,19].
9

3
.5. Effect of agitation speed on conversion yield of paracetamol
In order to investigate the effect of agitation speed on the reaction we carried out reactions at
different speed in the range of 100 rpm to 400 rpm, keeping all other parameters constant like,
temperature 60ºC, molar ratio 1:6:5 and ultrasound frequency 22 kHz, power 125W and duty
cycle 50%. The results showed that the effect of agitation speed did not display significant effect
on this reaction as the yields obtained at 100 rpm, 200 rpm, 300 rpm and 400 rpm gave the
percent yield of 54.95%, 55.62%, 56.91% and 55.54% respectively. As this is a homogenous
reaction, the mass transfer (physical effect) is not important. Another reason for this would be
due to the overlapped effect of ultrasound over stirring, in which effective collision of molecules
happens much more efficiently than that of stirring.
3
.6 Comparison of conventional and ultrasound assisted synthesis of paracetamol
Ultrasound assisted synthesis was found that as the amount of power delivered to the reaction
mixture increases, the rate of the reaction increases which claims, activation energy required for
the nucleophilic substitution has been delivered through cavitation. The optimization of various
reaction and ultrasound parameters was minimized the energy and time requirement of reaction.
Fig. 6 shows the comparison of % yield of paracetamol using conventional and UAS. UAS of
paracetamol was achieved at a lower temperature (60°C) and the time (150 min) without
formation of salt as the byproduct, while the conventional process requires high reaction
temperature (220ºC) and time (15h).
4
. Conclusions:
Here, ultrasound was utilized successfully to intensify the yield of paracetamol by using
hydroquinone, ammonium acetate and acetic acid as raw material. In the context of green
technology, use of ultrasound resulted into safe operation with shorter reaction time. The
1
0

synthesis of paracetamol without salt production and water as the by-product gives the upper
hand for its potential application. Optimization of parameters revealed that the percent yield of
5
7.72% can be obtained in 150 minutes by performing reaction in ultrasound bath. The use of
ultrasound bath can be helpful for achieving the better yield of the product. The chemical effects
due to cavitation phenomenon by ultrasound may be the reason for this reaction to proceed, as
the physical effects are generally observed with the heterogeneous reactions. The reaction
proceeds at relatively lower temperature than conventional method which is also additional
advantage.
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1
3

Figures caption
Fig. 1. Effect of temperature (℃) on conversion yield (%) of paracetamol at agitation speed of
3
00 rpm, molar ratio of hydroquinone to ammonium acetate and acetic acid 1:2:5 respectively,
ultrasound frequency 22 KHz, power 50 W and duty cycle 50%)
Fig. 2. Proposed mechanism pathway
Fig. 3. Effect of irradiation power (W) on conversion yield (%) of paracetamol at ultrasound
frequency 22 KHz, temperature 60℃, agitation speed of 300 rpm, molar ratio of hydroquinone to
ammonium acetate and acetic acid 1:2:5 respectively, and duty cycle 50%)
Fig. 4. Effect of molar ratio on conversion yield (%) of paracetamol at temperature 60℃,
agitation speed of 300 rpm, ultrasound frequency 22 KHz, power 125W, duty cycle 50%)
Fig. 5. Effect of duty cycle (%) on conversion yield (%) of paracetamol, at temperature 60℃,
agitation speed of 300 rpm, ultrasound frequency 22 KHz, ultrasound power 125W, and molar
ratio 1:6:5
Fig.6 Comparison of parameters for conventional and UAS of paracetamol
1
4

4
3
3
2
2
1
1
0
5
0
5
0
5
0
5
0
3
4
5
0°C
0°C
0°C
60°C
0°C
7
0
25
50
75
100
125
150
175
200
Time (min)
Fig. 1. Effect of temperature (℃) on conversion yield (%) of paracetamol at agitation speed of
00 rpm, molar ratio of hydroquinone to ammonium acetate and acetic acid 1:2:5 respectively,
ultrasound frequency 22 KHz, power 50 W and duty cycle 50%)
3
1
5

O
OH
O
O
HN
O
NH2
+
-
NH4
H N
HO
2
O
OH
OH
APAP
OH
HQ
PAP
Fig. 2. Proposed mechanism pathway
1
6

5
4
3
2
1
0
0
0
0
0
0
5
7
1
1
1
0 W
5 W
00 W
25 W
50 W
0
25
50
75
100
Time (min)
125
150
175
200
Fig. 3. Effect of irradiation power (W) on conversion yield (%) of paracetamol at ultrasound
frequency 22 KHz, temperature 60℃, agitation speed of 300 rpm, molar ratio of hydroquinone to
ammonium acetate and acetic acid 1:2:5 respectively, and duty cycle 50%)
1
7

7
6
5
4
3
2
1
0
0
0
0
0
0
0
0
01:02:05
01:03:05
01:04:05
01:06:05
01:08:05
01:10:05
0
25
50
75
100
125
150
175
200
Time (min)
Fig. 4. Effect of molar ratio on conversion yield (%) of paracetamol at temperature 60°C,
agitation speed of 300 rpm, ultrasound frequency 22 KHz, power 125W, duty cycle 50%)
1
8

7
6
5
4
3
2
1
0
0
0
0
0
0
0
0
4
0%
50%
6
7
8
0%
0%
0%
0
25
50
75
100
125
150
175
200
Time (min)
Fig. 5. Effect of duty cycle (%) on conversion yield (%) of paracetamol, at temperature 60°C,
agitation speed of 300 rpm, ultrasound frequency 22 KHz, ultrasound power 125W, and molar
ratio 1:6:5
1
9

70
60
50
40
30
20
10
0
UAS
Conventional
0
200
400
600
800
1000
Time (min)
Fig.6 Comparison of parameters for conventional and UAS of paracetamol
2
0

O
OH
O
HN
O
+
-
NH4
H N
2
O
O
US, 60°C
OH
HO
OH
APAP
HQ
Graphical abstract: Direct amidation of hydroquinone
2
1

Research Highlights


Optimization of various reaction and ultrasound parameters was performed
UAS of paracetamol was achieved without formation of salt as a byproduct, making
reaction green and inherently safer


Ultrasound assisted synthesis minimizes the energy and time requirement
Cavitation can also be used to intensify the synthesis other pharmaceutical compounds
2
2