Journal of the Taiwan Institute of Chemical Engineers 119 (2021) 1
5

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Journal of the Taiwan Institute of Chemical Engineers

journal homepage: www.elsevier.com/locate/jtice

A case study on the partitioning of pharmaceutical compound naproxen

in edible oil-water system in the presence of ionic and non-ionic
surfactants
Yeganeh Nachari, Morteza Jabbari*
School of Chemistry, Damghan University, Damghan 36716-41167, Iran

A R T I C L E I N F O A B S T R A C T

Article History: The partitioning coefficient is a physicochemical quantity which gives important information about the dis-
Received 16 December 2020 tribution and efficiency of bioactive compounds in various biological systems. The present work aims at
Revised 10 February 2021 detailed investigation of the partition process of drug naproxen between edible oils (olive, sunflower, ses-
Accepted 10 February 2021
ame) and water in the presence of two differently charged surfactants consisting of SDS (sodium dodecylsul-
Available online 13 February 2021
fate), DTAB (n-dodecyltrimethylammonium bromide) and non-ionic surfactant Brij 35 (polyethylene glycol
Keywords: dodecyl ether). The evaluation was done at atmospheric pressure and 25.0 °C by using UV
Vis spectrometric
Partition coefficient and shake-flask techniques. In this work, all the surfactants are used in a concentration below their CMC due
Naproxen to the turbidity that occurs in the biphasic oil-water systems in the concentrations above their CMC. The
Surfactant effect experimental results obtained indicate that the oil-water partition coefficient (Koil/w) of naproxen reduce
Edible oil-water system with rising the surfactants concentration in medium irrespective of the oil employed. Moreover, these values
Gibbs free energy of partitioning in the surfactant media are lower in comparison with surfactant free medium. The values of standard Gibbs
free energy of the transfer (DGBw ! oil ) calculated for all binary oil-water systems have negative sign which
indicates the preference of this drug for oil phase and thus spontaneous partitioning process. The surfactant
effect on the partition coefficients of drug is analyzed in terms of the intermolecular interactions such as
hydrogen bonding, dispersion and electrostatic forces between the drug and the surfactant.
© 2021 Taiwan Institute of Chemical Engineers. Published by Elsevier B.V. All rights reserved.

1. Introduction edible oil-water partition coefficients closely correlate with how

Naproxen (C14H14O3) with chemical name 2-(6-methoxynaphtha-
len-2-yl) propanoic acid (Fig. 1) is a well-known nonsteroidal anti-
inflammatory drug that is widely used in medicine and veterinary
medicine [1]. There is little physicochemical information about the
transfer processes of naproxen, despite the fact that it is widely used
in different medical conditions [2]. The study of the process of trans-
fer of pharmaceutical compounds in order to measure the partition
coefficient in organic-aqueous systems can be add valuable informa-
tion to medicinal chemistry. Such data can be used for the prediction
of absorption, membrane permeability, and in vivo drug distribution
[3,4]. The partition coefficient of the drug is defined as a quantitative
parameter for assessing all its interactions with the two phases in
which it is dissolved. These interactions consist of hydrogen bonding,
electrostatic and dispersion forces, etc. Understanding the drugs` par-
titioning behavior of the drugs in different systems as a function of
their hydrophilic or hydrophobic nature is important in various areas
such as medicine, pharmaceutical and food industries [5-7]. The
* Corresponding author.
E-mail address: m_jabari@du.ac.ir (M. Jabbari).
drugs partition into rats and human tissues. Also they may be better
than the octanol-water partition coefficient to predict the partition
coefficients of lipid tissue plasma [8]. To evaluate the hydrophobicity
of the drugs, the oil-water partition coefficient (Koil/w), as a funda-
mental physicochemical parameter, is measured. The Koil/w is an
indicative parameter that classifies different types of molecules by
their hydrophobicity [9]. Surfactants (surface active agents) are mole-
cules with amphiphilic nature that can increase the solubility, mobil-
ity, and biodegradation of hydrophobic or organic compounds as
they reduce the surface and interfacial tensions. The surfactants are
classified based on the charge type of the head groups into cationic,
anionic, zwitterionic (ampholytic) or non-ionic. In an aqueous
medium, the micelles are formed spontaneously once a delicate bal-
ance of intermolecular forces governs the interactions responsible for
surfactant self-assembly. This occurs when the surfactant concentra-
tions are above the critical micelle concentrations (CMC) [10,11]. Due
to lack of any electrical charges, non-ionic surfactants, have lower
CMC values than ionic surfactants with similar hydrocarbon chains
[12]. Moreover, the hydrophilic part in non-ionic surfactants gener-
ally contains the derivatives of polyoxypropylene, polyoxyethylene,
or polyol.

https://doi.org/10.1016/j.jtice.2021.02.012
1876-1070/© 2021 Taiwan Institute of Chemical Engineers. Published by Elsevier B.V. All rights reserved.
2 Y. Nachari and M. Jabbari / Journal of the Taiwan Institute of Chemical Engineers 119 (2021) 1
5
Fig. 1. Molecular structure of the pharmaceutical compound naproxen.
The literature survey brings us little information about the effects
of surfactants on the drugs distribution [4,13
16], where in most
cases the partitioning coefficient value is experimentally determined
only in octanol/water system and no mechanistic explanation is given
for the observed effects from a molecular interaction aspect. Hence,
in the present work we measured the partition in olive
,
sunflower
, and sesame oil-water binary systems of the drug nap-
roxen using the shake flask experiments in the presence of different
surfactants varying in hydrophilic head groups (cationic, anionic and
non-ionic). The effect of concentration and head group charge of sur-
factants on the partition process of this drug is analyzed to under-
stand the role of various molecular interactions between the
surfactants and the drug in partitioning behavior of the naproxen.
These measurements will provide an extension of the available parti-
tion coefficients in the surfactant systems.
2. Experimental section
2.1. Materials and apparatus
Naproxen (NAP) was received as a gift sample from Damavand
Darou Co. (Damghan, Iran) with purity  99.9% and used as received.
The amphiphilic surfactants Brij 35 (C12H25(OCH2CH2)23OH;
CMC = 0.09 mM, purity 99%), DTAB (C12H25N(CH3)3Br;
CMC = 14.50 mM, purity 98%) and SDS (C12H25SO4Na;
Fig. 2. Calibration curves of NAP in (a) olive oil (b) sunflower oil (c) sesame oil phases and (d) aqueous phase at 25 °C and ionic strength of 150 mM NaCl.
CMC = 8.11 mM, purity 99%) were obtained from Sigma-Aldrich.
The organic solvents 1-butanol and ethanol of the highest purity
(99.9%) were purchased from Merck. Edible olive, sesame and sun-
flower oils with reliable purity were obtained from one of local Dam-
ghan markets. The double distilled water with conductivity lower
than 2.0 mS cm
1 was used throughout all experiments. The absor-
bance of the sample solutions was obtained using a
UV
Vis spectrophotometer (Perkin-Elmer model Lambda 25) in con-
junction with a LabTech LCB-R08 thermo-circulator.
2.2. Procedure and measurements
2.2.1. Determination of molar absorbance coefficient of NAP
The calibration curve of absorbance versus concentration is
obtained ahead of partitioning measurements to estimate the con-
centration of drug dissolved in the aqueous and oil phases. This is
done using standard drug solutions that have been prepared in the
appropriate concentration range. To obtain the calibration curve for
oil phase, first the absorbance of an aliquot ( 100 mL) of the oil frac-
tion of the binary oil/water mixtures prepared without NAP is mea-
sured after dilution to 1 mL by ethanol/butanol (1:1) mixture. An
equal volume, this time from NAP stock solution prepared in oil
(3.3 mM or 4.9 mM respectively for sesame oil or olive and sunflower
oils) is diluted to 1.0 mL by ethanol/butanol mixture and its absor-
bance is measured. At each step of adding incrementally increasing
amounts (0.2 mL) of ethanol/butanol mixture to the solution, the
absorbance is recorded. For aqueous phase, a step-by-step dilution is
performed on a stock solution of NAP prepared in water
(6.8 £ 10
2 mM) to measure its absorbance at each step.
Fig. 2 shows the typical calibration curves obtained. Based on the
Beer
Lambert’s law, the molar absorbance coefficient (e) value of the
drug NAP at the maximum wavelength (λmax=270 nm and 331 nm
for aqueous and oil phases, respectively) is obtained from the stan-
dard curve slope. The values of molar absorbance coefficient for NAP
 Y. Nachari and M. Jabbari / Journal of the Taiwan Institute of Chemical Engineers 119 (2021) 1
5 3

are 2229.2, 2840.0, 1706.9 and 5751.7 M
1 cm
1 in olive, sunflower, Table 2
sesame oils and water phases, respectively. The partition coefficient and standard Gibbs free energy of partitioning values of
NAP in sunflower oil-water systems in the presence and absence of different surfac-
tants at 25 °C and ionic strength of 150 mM NaCl.
2.2.2. Oil-water partition coefficient assay
The partition coefficients of NAP between edible oils and water were log Koil/w DGBw ! oil (kJ mol
1)
derived by modifying the method suggested by Freiría-Ga ndara et al. surfactant free 1.719
9.812
[5], which employs the shake-flask method to measure the partition
[surfactant] (mM) SDS Brij 35 DTAB SDS Brij 35 DTAB
coefficients in binary oil-water systems for a number of bioantioxidants.
The oil-water partition coefficient of the drug NAP is measured in vari- 0.10 1.020 0.864 0.531
5.821
4.933
3.031
0.08 1.145 1.091 0.809
6.536
6.227
4.616
ous concentrations of the surfactants SDS, DTAB and Brij 35 in range
0.06 1.211 1.151 0.852
6.911
6.568
4.862
0.02
0.1 mM in ionic strength of 150 mM NaCl. All surfactants in this 0.04 1.238 1.200 0.996
7.069
6.848
5.686
work are used in a concentration below their CMC due to the turbidity 0.02 1.269 1.237 1.104
7.246
7.062
6.301
that occurs in the concentrations above CMC in the biphasic oil-water
systems. The hydrophobic drug NAP is dissolved directly in turn in ses-
ame oil or olive and sunflower oils to obtain concentration of 3.3 mM or Table 3
The sesame oil-water partition coefficient and standard Gibbs free energy of parti-
4.9 mM respectively. A 1.0 mL of the solution is diluted by adding aque-
tioning values of NAP in the presence and absence of different surfactants at 25 °C
ous surfactants solutions (to reach to desired concentration of surfac- and ionic strength of 150 mM NaCl.
tant) and NaCl solution (to adjust ionic strength) to 10 mL for preparing
1:9 (oil:water, v/v) mixtures. After several minutes of stirring by means log Koil/w DGBw ! oil (kJ mol
1)
of a high-speed rotor, the mixtures allowed stand for at least 48 h to surfactant free 1.534
8.758
reach equilibrium between the phases. After this time, the oil and aque-
[surfactant] (mM) SDS Brij 35 DTAB SDS Brij 35 DTAB
ous phases were separated by centrifugation to determine the NAP con-
centration in these two phases by using UV
vis spectrophotometry via 0.10 1.405 1.378 1.004
8.023
7.868
5.729
0.08 1.467 1.461 1.119
8.376
8.343
6.389
previously obtained calibration curves. Each of the experiments is
0.06 1.504 1.480 1.239
8.587
8.451
7.074
repeated at least three times. 0.04 1.511 1.500 1.329
8.627
8.566
7.587
0.02 1.526 1.511 1.374
8.714
8.626
7.847
3. Results and discussion

3.1. Data of partition coefficients 3.2. Standard Gibbs free energy of partitioning

In biphasic oil-water system, NAP molecules distribute between
water and the oil phase. The oil-water partition coefficient (Koil/w) for
drug NAP is the ratio of the NAP concentration in oil phase to its con-
centration in aqueous phase after an equilibrium is reached. The Koil/
w value in logarithmic form is calculated as [5,17]

water biphasic system is useful for estimating the needed energy of
log Koil=w ¼ log ½NAPoil =½NAPw ð1Þ
where [NAP]oil and [NAP]w represent equilibrium concentrations of
the partitioned drug NAP in the oil phase and aqueous phase, respec-
tively. These concentrations are assayed by the calibration curve
obtained for the drug in each of phases. The values of oil-water partition
coefficient of NAP in the surfactant media used at the temperature 25 °C
are reported in Tables 1, 2 and 3 respectively for binary olive-, sun-
flower- and sesame-water systems. Unfortunately, to date, no data for
the partitioning of the drug NAP in edible oil-water systems in the pres-
ence of surfactants have been reported in the literature for comparison.
According to the data shown in Tables 1, 2 and 3, by rising the
concentration of each surfactant the log Koil/w values of drug
decrease. Moreover, within the surfactant concentrations tested, the
magnitude of NAP partition coefficient is in the order of SDS > Brij 35
> DTAB.
Table 1
The partition coefficient and standard Gibbs free energy of the partitioning values of
NAP in binary olive oil-water systems in the presence and absence of different sur-
factants at 25 °C and ionic strength of 150 mM NaCl.
log Koil/w DGBw ! oil (kJ mol
1)
surfactant free 1.729
9.870
[surfactant] (mM) SDS Brij 35 DTAB SDS Brij 35 DTAB
Different factors that contribute to partition coefficients include
hydrophobic and dispersion forces, the solute’s hydrogen bond
acceptor (basicity), hydrogen bond donor (acidity), and polarizability
which shows the induction forces and orientation. Therefore, analyz-
ing the partitioning behavior of a solute in the nonpolar solvent/
nonpolar molecules that have hydrophobic contacts with water [18-
20]. One of the thermodynamic functions which describes this energy
cost is the standard Gibbs free energy of transfer (DGBw ! oil ) of a solute
from water medium (w) to an organic (oil) phase which both are in
an equilibrium. It also provides a quantitative measurement of the
relative hydrophobicity of the solute as well as the phases [21]. The
relationship between Gibbs free energy of transfer of a component
from one phase to another and its partition coefficient at a constant
temperature can be predicted as follows [4]:
DGBw ! oil ¼
2:303RT logKoil=w ð2Þ
where T is the absolute temperature, R stands the constant of the gas-
ses (8.3145 J K
1 mol
1) and Koil/w represents the partition coeffi-
cient. The DGBw ! oil values for all binary oil-water systems are
calculated and the results obtained are listed in Tables 1, 2 and 3.
According to these Tables, DGBw ! oil is negative in sign that indicates
the preference of this drug for oil phase and thus spontaneous trans-
fer process. The highest DGBw ! oil values corresponded to the SDS sys-
tem, confirming the transfer process of negatively-charged drug NAP
from aqueous phase containing SDS surfactant to oil phase is energet-
ically more favorable, due to repulsive forces between the negatively-
charged head groups of SDS and the drug. While the lower values
DGBw ! oil are observed for Brij 35 and DTAB surfactant systems,
respectively.

0.10 1.465 1.082 1.073
8.362
6.175
6.124

0.08 1.484 1.177 1.103
8.474
6.717
6.300 3.4. Surfactant effect on values of koil/w
0.06 1.500 1.289 1.128
8.565
7.359
6.439
0.04 1.507 1.354 1.139
8.604
7.730
6.500
0.02 1.519 1.385 1.145
8.671
7.909
6.539 As shown in Fig. 3, the increase in surfactant contents resulted in
decreasing free NAP concentration in oil phase and so decreasing the
4 Y. Nachari and M. Jabbari / Journal of the Taiwan Institute of Chemical Engineers 119 (2021) 1
5

Fig. 3. Influence of the surfactant concentration on the partition coefficient of NAP in biphasic (a) olive oil- (b) sunflower oil- (c) sesame oil-water systems at 25 °C and ionic
strength of 150 mM NaCl; the lines are drawn to guide the eye.

NAP partition coefficients in all surfactant solutions. The surfactants
can potentially transfer from aqueous phase to the oil phase and
even locate themselves at the oil-water interface [17]. This can
explain the highly non-linear behaviors in Fig. 3 especially those of
the neutral surfactant. Moreover, an increase in the surfactant con-
centration at high concentration will not have a strong effect in
reducing partition coefficient of the drug due to surfactant transfer-
ring in the oil phase.
According to Tables 1-3, among the surfactants tested, NAP parti-
tion coefficient is the highest in SDS solutions and the lowest in DTAB
solutions at the identical concentration of the surfactants. Moreover,
irrespective of the edible oil type, the drugs` partition coefficients in
the surfactant media are lower than those in the surfactant free
medium. These results all reflect the surfactant-dependent property
of the NAP partitioning.
The drug NAP is a compound with low solubility in water (25 mg
L
1 at room temperature [3]). In addition, this drug has been known
as a weak acidic drug (pKa=4.40 [22]), thus in the neutral aqueous
medium (pH ~ 6.8), its carboxylic OH group can dissociate and form a
mixture of neutral and anionic species of the drug. Therefore, there

Fig. 4. A schematic diagram of possible interactions and orientation of the drug NAP in the presence of anionic SDS, cationic DTAB and non-ionic Brij 35 surfactants.
 Y. Nachari and M. Jabbari / Journal of the Taiwan Institute of Chemical Engineers 119 (2021) 1
5
are probably interactions between the ionized drug NAP with surfac-
tant systems which may be of type hydrogen bonding, hydrophobic
and electrostatic forces [23-25]. On the other hand, according to the
literature reports, the dissociation constant (Ka) of a weak acid in the
oil solutions is typically 5
6 times smaller than those in the aqueous
solution [26]. Thus, we ignore the ionization of weak acids in the oil
phase and represent the possible orientations between the drug NAP
and surfactant system in aqueous phase schematically in Fig. 4. In
aqueous phase, the surfactant molecules stay close to surface due to
having non-polar hydrocarbon chain. The possible orientation and
interactions of NAP molecule in aqueous phase in the presence of sur-
factants SDS, DTAB and Brij 35 is such that its negatively-charged car-
boxylic group binds to the outer section (hydrophilic) of surfactants
surface by electrostatic or hydrogen-bonding interactions, while the
non-polar part of drug drawn into the inner layer (hydrophobic) with
the aid of the hydrophobic interactions.
As described before, comparison between cationic, anionic and
non-ionic surfactant media shows that the log Koil/w values of NAP
has the order SDS > Brij 35 > DTAB in binary edible oil-water sys-
tems. The drug NAP interacts attractively with the surface of surfac-
tant DTAB via negatively-charged carboxylic group present in its
structure, while in the presence of SDS, electrostatic repulsions exist
between negatively-charged head groups of SDS and the carboxylic
group of NAP. This transfers more NAP from oil to aqueous phase in
the presence of DTAB and therefore the concentration of drug in
aqueous phase increases. The partition coefficients in DTAB medium
are lower than those in Brij 35 system because of stronger electro-
static interactions between NAP and DTAB in aqueous phase. Accord-
ingly, our data reveals that at higher DTAB content, the partition
coefficients decrease gradually, which can be attributed to stronger
electrostatic interactions.
Moreover, the order of increasing log Koil/w values in binary oil/
water media are as follows: olive oil/water > sesame oil/water > sun-
flower oil/water. This is probably due to difference in the solubility of
NAP in the edible oils used. Based on the results obtained, among the
edible oils under study, the drug NAP has the most solubility in olive
oil and the lowest solubility in sunflower oil.
Conclusions
Poor aqueous solubility and lipophilicity of drugs/bioactives limit
their application in drug formulation and delivery development. In
this study, the lipophilicity of the minimally soluble drug compound
naproxen in terms of partition coefficients has been determined in
binary edible oil-water systems in the presence of anionic (SDS), cat-
ionic (DTAB) and non-ionic (Brij 35) surfactants. The findings
obtained in the amphiphilic systems reveal that the log Koil/w values
of drug in the surfactant media are lower in comparison with surfac-
tant free medium, irrespective of the edible oil type. Moreover, the
anionic SDS surfactant shows the highest log Koil/w value for NAP as a
result of electrostatic repulsions between the drug and the negative
charge of surfactant head group, whereas the cationic DTAB and non-
ionic Brij 35 surfactant provided lower log Koil/w values, respectively.
The findings of present study indicate that NAP partition coefficient
is function of a series factors such as surfactant type, surfactant con-
centration, and vegetable oil type used.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
5
Acknowledgments
The authors appreciate Damavand Darou Pharmaceutical Chemi-
cals Co. (Damghan, Iran) for providing the drug naproxen, and also
the Research Council of Damghan University for facilitating the
equipment and laboratory facilities.
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