Accepted Manuscript

Title: Micellar and interfacial properties of amphiphilic

drug-non-ionic surfactants mixed systems: surface tension,
fluorescence and UV–visible studies

Authors: Naved Azum, Malik Abdul Rub, Abdullah M. Asiri,

Wafa Abubaker Bawazeer

PII: S0927-7757(17)30235-2
DOI: http://dx.doi.org/doi:10.1016/j.colsurfa.2017.02.093
Reference: COLSUA 21448

To appear in: Colloids and Surfaces A: Physicochem. Eng. Aspects

Received date: 30-11-2016

Revised date: 26-2-2017
Accepted date: 28-2-2017

Please cite this article as: Naved Azum, Malik Abdul Rub, Abdullah M.Asiri,
Wafa Abubaker Bawazeer, Micellar and interfacial properties of amphiphilic drug-
non-ionic surfactants mixed systems: surface tension, fluorescence and UV–visible
studies, Colloids and Surfaces A: Physicochemical and Engineering Aspects
http://dx.doi.org/10.1016/j.colsurfa.2017.02.093

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Micellar and interfacial properties of amphiphilic drug‒non-ionic surfactants mixed
systems: surface tension, fluorescence and UV‒visible studies

Naved Azum1,2*, Malik Abdul Rub1,2, Abdullah M. Asiri1,2, Wafa Abubaker Bawazeer2

1
Center of Excellence for Advanced Materials Research, King Abdulaziz University,
Jeddah 21589, Saudi Arabia
2
Chemistry Department, Faculty of Science, King Abdulaziz University, Jeddah 21589,
Saudi Arabia

*Corresponding author. Tel.: +966 126473648

E-mail address: navedazum@gmail.com

1|Page
Graphical Abstract

The aggregates structures of amphiphiles, predicted from packing parameter.

2|Page
Research Highlights

1. Interactions of CPZ with non-ionic surfactants have been studied.

2. It has many side effects therefore; need a carrier for safe drug delivery.

3. The negative β values show attractive interactions between drug and surfactants.

4. The results have been applicability in the model drug delivery systems.

3|Page
ABSTRACT

This study reports the influence of non-ionic surfactants (TX-100 and TX-114) on the
CPZ by surface tension, fluorescence and UV-visible spectra to explore their applications
as drug delivery vehicles. The synergism is indicated by the values of the interaction
parameters and activity coefficients, which are negative and less than unity, respectively.
The ideal micellar mole fraction values of CPZ are less than the experimental values,
confirming the high contribution of CPZ in mixed systems. The stability of these mixed
systems is demonstrated by negative free energies of mixing.

Keywords: Amphiphilic drug, Non-ionic surfactants, Surface tension, Fluorescence, UV-

visible

4|Page
1. Introduction

Amphiphiles or surfactants, being amphiphilic in nature, have an important place in

the scientific world and find multiple applications in industry and laboratories. The two
main fundamental properties of amphiphiles are the ability to adsorb at interfaces in an
oriented fashion and to form micelles [1–3]. The dynamic behaviors of many systems
(stability of foams, the droplet size in jets and sprays, the spreading of drops on solid
surfaces, and the smooth coating of multiple layers) are controlled by the adsorption of
surfactants at the air–water interface [4–6]. Many micelles have catalytic properties and
are structurally similar to that of globular proteins and biological membranes [7–9].
Amphiphiles are employed by organic chemists and biochemists in different industrial
processes, such as laundry [10], emulsion formation [11], corrosion prevention [12] and
firefighting [13].

However, mixed amphiphilic systems are experienced in almost all applications of

amphiphiles and the mixed systems behave better than single amphiphiles [14–18]. The
amphiphilic systems used in industry are typically mixtures of different chemical species,
such as ionic and non-ionic amphiphiles, electrolytes, dyes and fillers. The ionic strength,
pH, viscosity and other beneficial physicochemical properties are acquired by mixed
systems. Mixed systems of different amphiphiles often show synergism. The physical
properties like surface tension reduction efficiency and effectiveness, foaming, wetting,
solubilizing, detergency, are also associated with synergism [2]. It can be ascribed to non-
ideal mixing effects in the amphiphile films and in the micellar aggregates, which result
in interfacial tensions and in critical micellization concentrations (cmc) which is
substantially lower, than it for the used surfactants. The ionic‒non-ionic mixed systems
are more interesting from the fundamental point of view because they often exhibit
highly non-ideal behavior. The addition of a non-ionic surfactant to an ionic amphiphile
can reduce the electrostatic repulsions between the charged surfactant heads and greatly
facilitate mixed micelle formation. Among the amphiphiles, non-ionic amphiphiles
having ethylene oxide chains (hydrophilic group) are important class of amphiphiles (Fig.

5|Page
1). Because of their fascinating properties, non-ionic amphiphiles are used in industrial
and pharmaceutical formulations. Similar to other amphiphiles, non-ionic amphiphiles
also form thermodynamically stable nano-scale assemblies called ‘micelles’ but at lower
concentration. If we use an amphiphilic drug with a carrier (surfactants), then the drug
efficiency increases with fewer side effects. The superior behavior of the drug + carrier
systems is due to the interaction between the components.

Chlorpromazine hydrochloride (CPZ) is an amphiphilic phenothiazine drug having

great chemical, medical and a variety of biological properties [19]. It is employed to treat
schizophrenia, disorders with psychosis, and mania. Other important uses of CPZ are to
prevent and treat nausea and vomiting. The chemical balance in the brain can be
controlled by CPZ. It is an amphiphilic cationic compound, under current physiological
conditions, which consist of hydrophobic nitrogen containing a charged amino group
(Fig. 1). The study of phenothiazine aggregates has attracted much attention because of
their photosensitizing effects in patients under therapy. The phenothiazine compounds
have interesting physicochemical behavior associated with their capacity to change the
properties of natural and model bio-membranes. CPZ is a tricyclic antipsychotic drug
having drowsiness, dizziness, dry mouth, blurred vision, and tiredness side effects [20].
In addition to this, CPZ induces phospholipidosis, which is the excessive intracellular
accumulation of phospholipids [21]. The interaction occurs between the negative
phosphate oxygen of the lipids found in the body and the protonated amine group of CPZ.
To reduce these side effects, CPZ is preferentially used with a carrier.

Thus, the purpose of our study is to investigate the adsorption and micellization of
cationic amphiphilic drug (CPZ) mixed with non-ionic surfactants (TX-100 and TX-114).
Such explorations are a guide to depicting the involvement of the individual components
in the mixed aggregates and mixed adsorbed monolayer. The applicability of a
thermodynamic model for binary systems is also considered. The analysis of data has
been made in the light of various theoretical models, including those of Rubing, Clint,
and Maeda.

6|Page
2. Experimental methods and materials

2.1 Materials

All the chemicals were employed as obtained without further purification

throughout the study. Chlorpromazine hydrochloride (CPZ), Triton X-100 (TX-100), and
Triton X-114 (TX-114) were the product of Sigma (USA) with a purity >98%. De-
ionized and double distilled water was when preparing stock solutions of single and
mixed amphilies solutions. Pure amphiphiles (CPZ, TX-100 and TX-114) solution were
prepared by diluting concentrated stock solutions (accurately weigh the compounds
according to the requirement). The mixer of solutions in different mole fractions (0.1, 0.3,
0.5, 0.7 and 0.9) were prepared by mixing pure solutions (CPZ, TX-100 and TX-114) and
kept at least for 12 h to equilibrate. The surface tension at each mole fraction was
measured by successive additions of a concentrated solution of amphiphile mixture in
pure water by using a Hamilton syringe. All experiments were carried out at 298.15 K.

2.2 Surface tension measurements

The surface tension of CPZ, TX-100, TX-114 and their binary mixtures were
obtained by using Attension tensiometer (Sigma 701, Germany) at 298.15 K in the ring
detachment method. The temperature of the studied solution was kept constant within ±
0.1 K by regularly circulating thermostated water through a jacketed vessel. Attension
tensiometer work on Du Nouy principle. Accordingly the force to lift the ring from the
surface of a liquid is related to the surface tension of that liquid by the relation:
F=2π (r1+r2) γ (1)

where r1 and r2 are the radius of the inner ring and outer ring of the liquid film
respectively. The concentration of a solution was varied by the aliquot addition of stock
surfactant solution of known concentration to a known volume of solvent in the vessel.
For each set of experiments, the ring was cleaned by heating it in an ethanol flame. The
measured surface tension values were plotted as a function of the logarithm of surfactant
concentration (Fig. 2). The accuracy of the measurements was within ± 0.1 m Nm–1.

7|Page
2.3 Fluorescence measurements

All fluorescence measurements were performed on Hitachi F-7000 spectrometer.

This apparatus is equipped with 1500 W xenon lamp as the excited source. Fluorescence
data were collected by using excitation wavelength of 315 nm. The size of both emission
and excitation slits were at 5 nm. For all the measurements, a 10-mm quartz cell was
used.

2.4 UV-visible measurements

The absorbance of CPZ solution with and without surfactants was measured over a
wide range of surfactant concentrations. The absorbance data was obtained using double
beam UV-visible spectrometer (Themo Scientific, Evolution 300) and the base line
correction was made by using de-ionized water. The absorbance of solutions was noted at
equilibrium temperature of 298.15 K.

3. Results and discussion

3.1 Surfactant mixtures at the air–water interface

The alignment or position of adsorbed amphiphiles (drug as well as surfactants) at

the surface decreases the surface tension of the aqueous phase (Fig. 2). The breakdown of
hydrogen bonding at the surface is associated with decrease in surface tension. The
increase in the concentration of adsorbed amphiphiles leads to further decrease in surface
tension. The surface excess concentration (Γmax) of the amphiphile [22] can be
determined by the change in surface tension with respect to change in amphiphile
concentration. For dilute solutions, the Gibbs equation can be written as:

1 𝑑𝛾
Γ𝑚𝑎𝑥 =– lim𝐶→𝑐𝑚𝑐 ( ) (2)
2.303𝑛𝑅𝑇 𝑑𝑙𝑜𝑔𝑆

8|Page
where γ is the surface tension in mN m–1, R is the universal gas constant (8.314 J mol–1 K–
1
), T is the absolute temperature, S is the amphiphile molar concentration, n is the number
𝑑𝛾
of species at the air–solution interface after amphiphile dissociation and is the slope
𝑑𝑙𝑜𝑔𝑆

of straight linear part of this curve which corresponds to saturated monolayer of

amphiphiles at the air-water interface.

For non-ionic surfactants n is taken as 1. In the case of CPZ, considering CPZ as a

strong electrolyte, it is dissociated in aqueous solution into two parts; one is univalent
amphiphile ion and the other univalent counterion in the absence of a swamping
electrolyte. Therefore, for CPZ, n is taken as 2 and Eq. (2) assumes the form:

1 𝑑𝛾
Γ𝑚𝑎𝑥 =– lim𝐶→𝑐𝑚𝑐 ( ) (3)
4.606𝑅𝑇 𝑑𝑙𝑜𝑔𝑆

In order to examine the details of adsorption behavior of mixed systems,

evaluation of surface excess concentration, Γmax, and the analysis of composition of
adsorbed film phase are necessary. The total surface excess (Γmax(T) = Γmax(1) + Γmax(2))
can be derived for such a mixed system composed of 1-1 electrolyte type cationic
amphiphile and non-ionic surfactant [23, 24]:

1 𝑑𝛾
Γ𝑚𝑎𝑥 =– lim𝐶→𝑐𝑚𝑐 ( ) (4)
(2−𝑍2 )𝑅𝑇 𝑑𝑙𝑜𝑔𝑆

where Z2 denotes mole fraction of TX-100/TX-114 at the interface (Z2 = 1–Z1). From the
analogy with the derivation of Rubingh’s equation (15), we obtained the value of Z1 from
Rosen approach [3, 25]. The values of Z1 are listed in Table 1.

Γmax can be used to calculate the minimum area per molecule (Amin) by the
relation:

𝐴𝑚𝑖𝑛 = 1018 /(𝑁𝐴 𝛤𝑚𝑎𝑥 ) (5)

where NA is the Avogadro constant. The values of Γmax and Amin are shown in Table 1. The
Γmax and Amin parameters indicate the packing of amphiphiles, whether it is closely or

9|Page
loosely packed at the surface. The creation of a packed interfacially adsorbed mixed
monolayer and steric factor caused by the bulky group are the two associated phenomena
with these two parameters. It is confirmed from Table 1 that Γmax values for CPZ are
lower than for non-ionic surfactants, which means CPZ is less surface active than non-
ionic surfactants. The values of Γmax for the mixed systems (CPZ+TX-100/TX-114)
increases with the increase of the mole fraction of CPZ. This indicates monomers are
closely packed at the air–water interface in the presence of CPZ components in the mixed
systems. The more compact adsorbed mixed monolayer at the air–water interface is due
to the hydrophobic interactions between different hydrophobic tails. Because of the
hydrophobic interaction, molecules are being pumped towards the interface, which results
in higher surface concentration and lowers the occupied area per molecule at the
interface. The orientation perpendicular to the interface and close packing of interrelating
components at the air–water interface are due to the values of Amin for pure amphiphiles,
which are lower than its mixtures. Γmax and Amin values in case of TX-100 (2.423 x 10‒6
mol m‒2 and 0.685 nm2) are in good agreement to previous reported values (2.687 x 10‒6
mol m‒2 and 0.64 nm2) [26].
The values of Aideal are calculated using the relation
Aideal = Z1 A1 + (1-Z1) A2 (6)

where X1 is the micellar mole fraction of component one (CPZ). The values of Aideal are
shown in Table 1. The values are lower than the Amin, showing that the area occupied by
an amphiphilic head in this mixed system (CPZ+TX-100/TX-114) is greater than it is in
ideal mixing conditions and that is why a loose monolayer forms. The parameter pC20 is
the efficiency of interfacial adsorption [2]. It is the negative logarithm of C20. The C20
value can be defined as the concentration required decreasing the surface tension of a
pure solvent by 20 mN m-1. The larger the value of pC20, the better is the efficiency of a
system to adsorb at the air–water interface and to decrease the surface tension. The pC20
values of non-ionic surfactants are more than CPZ because of the greater hydrophobicity
of TX-100/TX-114 (Table 1). The pC20 values for pure surfactants (TX-100 and TX-114)

10 | P a g e
are also found to be in good harmony with earlier study [27]. The mixtures of CPZ+TX-
100/TX-114 have been found to be more surface active than pure CPZ. The surface
pressure at the cmc (πcmc), which is an index of surface tension reduction at the cmc, has
been calculated using the Eq.:
𝜋𝑐𝑚𝑐 = 𝛾0 − 𝛾𝑐𝑚𝑐 (7)
where 0 = the surface tension of water and cmc = the surface tension of surfactant
solution at cmc. The πcmc values thus calculated for various systems are recorded in Table
1. The values are found to decrease on addition of drug for present binary systems. This
may be ascribed to the lower tendency of the drug to adsorb at the air–liquid interface.

The packing parameter (p) calculated by Tanford’s formula [28] informs about the
shape of micelles in aqueous medium

𝑉0
𝑝= (8)
𝑙𝑐 𝐴𝑚𝑖𝑛

where V0, lc and Amin are the volume of hydrophobic group in the micellar core, length of
the hydrophobic group in the core, and minimum area per molecule at the air–water
interface respectively. The volume and length of the hydrophobic group can be calculated
using Tanford’s Eqs (9) and (10):

V0 = [27.4+26.9(nC–1)]2 (9)

lc = [1.54+1.265(nC–1)] (10)

where nC is the number of carbon atoms in the hydrocarbon chains of the components.
The p values (Table 1) can be used to predict the cumulative shape based on the geometry
of the monomer, such as spherical (0–0.33), cylindrical (0.33–0.5) and lamellar (0.5–1).
The value of CPZ and its mixtures with non-ionic surfactants are higher than 0.33, which
indicates the formation of cylindrical structure (Scheme 1) [28].

11 | P a g e
3.2 Critical micelle concentration

It is well understood, if we slowly add drops of amphiphilic solution, the surface

tension decreases till it reaches a minimum value. The concentration of surfactant where
that minimum attained is the point where extra surfactant ends up as micelles rather than
producing any further reduction in surface tension. This value is known as the critical
micelle concentration, cmc. Fig. 2 shows representative plots of surface tension versus
log of total surfactant concentration [STotal]. These curves are called ‘isotherm’ and can be
fitted to various equations. The values of cmc for CPZ, TX-100, TX-114 and mixtures
determined from isotherms of adsorption are given in Table 2. The values of cmc of pure
amphiphiles found to be close with the earlier reported values [27, 29, 30]. It is well
known that the cmc is a range rather than a single pinpointed value, so various methods
used for determination of the cmc often lead to different numerical estimates not only
because of measurement error. All the calculations for models applied in the present
study were performed using Microsoft Excel. The cmc value of CPZ is high in
comparison to nonionic surfactants. This phenomenon may be explained by the fact that
there is electrostatic repulsion between the charged head groups. These hydrophilic
repulsive forces are counteracted by the hydrophobic attractive forces due to the presence
of the hydrophobic tail. To minimize the electrostatic repulsive forces between the
charged head groups, a higher concentration of CPZ is required. However, in the case of
non-ionic molecules, the hydrophobic effect of the tail group is the main driving force for
micellization; hence a lower concentration is required to form micelles. In the mixed
micelle state, the mixed amphiphiles may show either ideal or non-ideal behavior at the
cmc. The properties of the ideal or non-ideal behavior of mixed micelles of the drug with
a non-ionic surfactant can be investigated by applying a pseudo-phase model [31].
According to the pseudo-phase model (molecular thermodynamics model) of mixed
micelles, the cmc of a binary mixture of components 1 and 2 can be expressed as a
function of the cmcs of the constituent pure amphiphiles as follows [32]:

12 | P a g e
 1 1 2
  (11)
cmcideal f1cmc1 f 2 cmc2

where α1 and α2 are the stoichiometric mole fractions of components (drug 1, and
surfactants 2) in binary mixtures, and cmc1, cmc2 are the cmc’s of CPZ and TX-100/TX-
114, respectively. f1 and f2 are activity coefficients of respective components in the mixed
micelle.
In the case of ideal behavior, f1 = f1 =1 and hence Eq. (11) reduces to the form:
1  
 1  2 (12)
cmcideal cmc1 cmc2

Equation (12) is valid for a mixed ideal system, for the non-ideal system there should be
deviation from the experimental value. Clint’s model is an underestimation and
idealization, which assumes that the particular components are non-interacting, and their
particular cmc values reflect their relative tendency towards mixed micellization. Any
deviation from cmcideal would, however, account for interactions among amphiphiles. A
positive deviation and negative deviation indicates antagonism and synergism,
respectively, in the system. Fig. 3 shows the deviation of cmcexp from cmcideal. Because
cmcideal > cmcexp the interaction between the two types of amphiphiles in the mixed
micelle at cmc was synergistic. This further suggests that the present mixtures were
formed by attractive interactions between the components. With an increase in the mole
fraction of CPZ in the mixtures, an increase in the cmc values for the mixtures has been
observed. This illustrates that in the formation of the mixed micelle, drug molecules
penetrat the micelle formed by the non-ionic amphiphiles. The infiltration of drug
molecule depends on the nature and polarity of the micellar core. In the case of ionic
surfactants the penetration of the drug molecule in the core is difficult due to electrostatic
repulsion between similar charges on the head group. So the ionic surfactants show lower
binding affinity. In the case of non-ionic surfactants the ethoxylate chains coil around the
charged head group of CPZ, screening the electrostatic repulsions and favoring micelle
formation resulting in high binding affinity.

13 | P a g e
 The variables f1 and f2 are the micellar activity coefficients, which can be
computed from the Eqs
𝑓1 = 𝑒𝑥𝑝[𝛽 (1 − 𝑋1 )2 ] (13)

𝑓2 = 𝑒𝑥𝑝[𝛽 (𝑋1 )2 ] (14)

The values of f1 and f2 are found to be less than unity for almost all systems,
indicating non-ideal behavior and an attractive interaction. X1 is the micellar mole
fraction of CPZ (component 1) of the mixed systems and can be calculated by
considering the regular solution theory (RST) and the treatment proposed by Rubingh
[33] by the following Eq.
[ X 12 ln(cmcexp1 / cmc1 X 1 )]
1 (15)
(1  X 1 ) 2 ln[cmcexp (1  1 ) / cmc2 (1  X 1 )]

The values of X1 were obtained by solving equation 15 iteratively. The ideal

contribution of the component in the formed mixed micellar system can be calculated in
term of mixed fraction in the ideal state as follows [34]:
α1 𝑐𝑚𝑐2
X ideal = (16)
α1 𝑐𝑚𝑐2 +α2 𝑐𝑚𝑐1

The values of X1 and X ideal are recorded in Table 2. It is clear from Table 2 that
the values of X1 deviate positively. A higher X1 than that of the X ideal value indicate that
mixed micelles have a higher contribution of CPZ in mixed micelle as expected, also
declare that the mixed system shows non-ideal behavior (synergism). The synergistic
effect occurs due to the difference in hydrophobicity of the mixed surfactant.
The β is an interaction parameter that reflects the magnitude of the degree
interaction between unlike components in the mixed micellar state. The value of β can
account for the deviation of the mixed system from ideality and β can be obtained from
the molecular thermodynamics theory from the relation:
  [ln (cmcexp 1 / cmc1 X 1 )] /(1  X 1 ) 2 (17)

The β values calculated by using Eq. 17 are given in Table 2.

14 | P a g e
 Synergism in the mixed micelle formation exists when the cmc of the mixture is
less than that of either amphiphile of the mixture. The conditions for this to exist in a
mixture of two amphiphiles are (a) β is negative and (b)  > ln(cmc1 / cmc2 ) . A

negative β value indicates attractive interactions among the mixed components; a positive
value means repulsive interactions while values close to zero indicate ideal mixing. In the
cationic and non-ionic amphiphiles there will be considerable electrostatic self-repulsion
on behalf of cationic and feeble steric self-repulsion in favor of non-ionic prior to mix
with each other. However, by mixing the components, the electrostatic self-repulsion of
the cationic drug will be replaced by ion-dipole attraction interaction involving the two
dissimilar hydrophilic groups of CPZ and TX-100/TX-114 amphiphiles, which results in
the negative values of β as well as the negative divergence of the cmc from ideal. The
criteria of synergism according to Rosen [3] determined by the above condition (  >

ln(cmc1 / cmc2 ) ) is also satisfied for current studied systems with few exceptions. In the

studied binary systems, comparing the average β values reveals that slightly less
synergism is observed in CPZ+TX-114, due to low β average value in comparison to
CPZ+TX-100 mixture.

3.3 Thermodynamic of micellization and interfacial adsorption

The tendency of surfactants to form micelles can be established based on standard
𝑜
free energy of micellization (∆𝐺𝑚𝑖𝑐 ). In the literature, there are many ways for
determination of this energy. Maeda [35] has proposed a new approach of standard free
energy determination for mixed micelles involving ionic species. In this approach, the
standard free energy of micellization for mixtures of two amphiphiles including one non-
ionic and one ionic component is given as a function of ionic amphiphile in the mixed
micelle by:
𝑜
∆𝐺𝑀𝑎𝑒𝑑𝑎 = 𝑅𝑇(𝐵𝑜 + 𝐵1 𝑋1 + 𝐵2 𝑋12 ) (18)
where Bo is the independent term related to cmc of non-ionic surfactant by Bo=lncmc2. B1
is a parameter related to the change in the standard free energy when an ionic monomer

15 | P a g e
enters the non-ionic micelle and places one non-ionic monomer from the micelle. B2 is
equivalent to β calculated from Eq. (17).
The phenomenon of change in standard free energy by the transfer of monomer
from the micelle is associated with two contributions: interaction between head groups
and between hydrocarbon chains. The first contribution is dominant, when the
hydrocarbon chains are of the same kind. However, when there is dissimilarity between
the hydrocarbon tails, the interaction between these tails becomes more significant and
makes the values of B1 negative. As reflected in Table 3 the calculated values of B1 are
positive. This means the contribution is caused by the interactions between the head
groups. Finally, the parameters B1 and B2 are related to the cmc values of pure systems by
the Eq:
ln(cmc1/ cmc2) = B1 + B2 (19)

The thermodynamics or energetic of micellization can be well interpreted by the

use of two well-known models (phase-separation and mass-actions models). For the ionic
surfactants, however, the mass-action approach is usually preferred and various
thermodynamic parameters may be deduced from the temperature dependence of the cmc
values. According to the mass-action model, the standard Gibbs free energy of
𝑜
micellization ( ∆𝐺𝑚𝑖𝑐 ) for ionic and non-ionic surfactant solutions is calculated using the
Eq [36]
𝑜
∆𝐺𝑚 = 𝑅𝑇𝑙𝑛𝑋𝑐𝑚𝑐 (20)
𝑜
where Xcmc is the cmc in mole fraction unit. It is observed that the ∆𝐺𝑚 are negative and
addition of non-ionic to the drug made the formation of mixed micelle easier. With
increase in the mole fraction of CPZ, these values become less negative (Table 3),
indicating that the micellization process becomes less spontaneous for all mixtures
𝑜
studied. The ∆𝐺𝑚 of pure non-ionic surfactants were found to be comparable with
previous reported values [27]. It is also clear from Table 3 that the values of standard free
energy of micellization estimated by Eqs 18 and 20 have very good agreement.

16 | P a g e
 𝑜
The standard free energy of adsorption, ∆𝐺𝑎𝑑 , can be determined by the different
methods. According to Langmuir, if the adsorbed molecules are immobile and adsorbed
on the sites in the interface, the area per adsorbed molecule will be related to the bulk
𝑜
concentration of the surfactant, and ∆𝐺𝑎𝑑 will satisfy
𝑜
𝐴0 𝐶 −∆𝐺𝑎𝑑
= 𝑒𝑥𝑝 ( ) (21)
𝐴−𝐴0 𝜔 𝑅𝑇

where A0 is the excluded area (the area of the interface unavailable to one molecule due to
the presence of another), ω is the number of water moles per dm3 and C is the amphiphile
concentration. The de Boer gave a statistical correction in Langmuir equation [30, 37]. If
the mobile adsorption isotherm are consider the modified equation can written as
𝑜
𝐴0 𝐴0 𝐶 −∆𝐺𝑎𝑑
𝑒𝑥𝑝 ( )= 𝑒𝑥𝑝 ( ) (22)
𝐴−𝐴0 𝐴−𝐴0 𝜔 𝑅𝑇

𝑜
The ∆𝐺𝑎𝑑 of pure amphiphiles were calculated by the Eq. (22) using A0 equal to 0.99,
𝑜
0.597 and 0.435nm for CPZ, TX-100 and TX-114, respectively. The ∆𝐺𝑎𝑑 values for
CPZ, TX-100 and TX-114 are found to be –36.045, –46.914 and –40.86 kJ/mol,
𝑜
respectively. The The ∆𝐺𝑎𝑑 for TX-100 determine by Janczuk et. al. (45.3 kJ/mol)[37]
tally with our result. The standard free energy of micellization calculated by Eq. (20) is
translated into the standard free energy of adsorption at the air-water interface using the
Eq [38-43]
𝑜 𝑜
∆𝐺𝑎𝑑 = ∆𝐺𝑚 − 𝜋𝑐𝑚𝑐 /Γ𝑚𝑎𝑥 (23)
𝑜
The agreement between the values of the ∆𝐺𝑎𝑑 for pure amphiphiles determine using
these two methods is near to each other. It appears that the negative value of standard free
energy of adsorption of CPZ determined by both methods is lower than that of non-ionic
𝑜
surfactants. It means that the CPZ has low adsorption efficiency. The ∆𝐺𝑎𝑑 values of
mixtures are calculated by the using equation (23) and listed in Table 3. These values are
negative, indicating that the process of adsorption as a spontaneous process. In addition,
𝑜 𝑜 𝑜
the magnitude is large and greater than∆𝐺𝑚𝑖𝑐 . The ratio, ∆𝐺𝑎𝑑 /∆𝐺𝑚𝑖𝑐 are greater than 1,
which indicates that the adsorption is primary while micellization is a secondary
phenomenon.
17 | P a g e
 Sugihara [44] proposed an equation to calculate Gmin (molar free energy at the
maximum adsorption attained at cmc) as
𝐺𝑚𝑖𝑛 = 𝐴𝑚𝑖𝑛 𝛾𝑐𝑚𝑐 𝑁𝐴 (24)
where, 𝛾𝑐𝑚𝑐 , Amin and NA are the surface tension of the surfactant system at equilibrium,
minimum surface area and the Avogadro constant, respectively. It may be defined as the
work needed to make a surface area per mole or free energy change accompanied by
transition from the bulk phase to the surface phase of the solution. The stability of a
surface depends on the Gmin value. The more thermodynamically stable surface is attained
at the lowest value of Gmin. The value of Gmin also measures the evaluation of synergism
in the mixed systems. It is clear from Table 3 that the values of Gmin are lower in
magnitude. It means thermodynamically stable surfaces are formed with synergistic
interaction.
The values of excess free energy of micellization were calculated using Eq. (25)
[45‒49]
Δ𝐺𝑒𝑥 = [𝑋1 ln 𝑓1 + (1 − 𝑋1 )𝑙𝑛𝑓2 ] (25)

The values are given in Table 3. The negative values suggest that the mixed micelles
formed are more thermodynamically stable than the micelles formed from the individual
amphiphiles [50‒52].
3.4 Fluorescence spectra
In phenothiazine compounds, charge transfer occurs and emission occurs at wavelengths
longer than absorption. The excitation of the fluorophore occurs from the ground state to
the first singlet state, where the electron density is transferred from the sulfur atom to
benzene rings, having greater π character. Because of this charge transfer, the torsion
angle and dipole moment of the excited state increases compared with the ground state.
Because of this, the wavelength of the fluorescence measurements of phenothiazine
increases. As can be seen from Fig. 4, the emission peak of CPZ is at 458 nm, and its
intensity gradually increases accompanied by a slight blue shift of the emission spectra
with the addition of surfactants. The change in emission spectra of CPZ in the presence of

18 | P a g e
non-ionic micellar media is shown in Fig 4. The plot of maximum fluorescence intensity
vs surfactant concentration is shown in Fig 5. The rapid increase of fluorescence intensity
is due to strong binding of nonionic surfactants with CPZ by the hydrophobic interaction.
The observed enhancement of intensity may be due to disaggregation of the monomers of
the compounds.

3.5 UV-visible absorption spectra

The UV-vis spectra provided important information about the environment. Fig. 6 shows
the absorption spectra of CPZ with an increase of [surfactant]. The peak of the spectra of
pure CPZ appears at 306 nm. This peak indicates the presence of a tricyclic region of the
antipsychotic drug CPZ. With the addition of TX-100/TX-114, the intensity of the
mixture decreases and the peak slightly shifts (blue shift). With the increase in [TX-
100/TX-114], the absorbance decreases rapidly owing to the binding of the monomer on
CPZ.
4. Conclusion
 The values of surface excess concentration (Γmax ) for the current mixed systems
increases (Amin decreases) with the increase of the CPZ mole fraction, confirming
that monomers are closely packed at the air‒water interface.
 The valuesof Aideal are lower than the Amin, showing that the area occupied by an
amphiphilic head in the mixed systems is greater than what it is to be in ideal
mixing condition and that’s why loose monolayer form.
 The ideal cmc values (cmcideal) are higher than the experimental values (cmcexp)
confirming that the interaction between the two types of amphiphiles in the mixed
micelle is synergistic (the present mixtures were formed by attractive interactions).
 The values of f1 and f2 are less than unity, indicating non-ideal behavior and
attractive interaction also confirmed by higher X1 than X1ideal values.

19 | P a g e
  The values of β were found to be negative showing that the interactions between
two components in the mixed micellar phase are less repulsive than the
interactions occurring between the individual components.
 The spontaneity of the current systems is confirmed by the negative values of the
𝑜
standard free energy of micellization (∆𝐺𝑚 ).
 The rapid increase of fluorescence intensity is due to strong binding of non-ionic
surfactants with CPZ by a hydrophobic interaction.

Acknowledgments

Chemistry Department and Centre of Excellence for Advanced Materials Research, King

Abdulaziz University, Jeddah are highly acknowledged.

20 | P a g e
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aqueous binary mixed surfactant systems. J. Oleo Sci. 57 (2008) 61-92.
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X-100 at the air-aqueous solution interface. Langmuir 11 (1995) 4515-4518.
[27] M.A. Rub, N. Azum, D. Kumar, A.M. Asiri, H.M. Marwani, Micellization and
micro-structural studies between amphiphilic drug ibuprofen with non-ionic
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of triton X-100 micelles in ethylene glycol-water solvents. Langmuir 17 (2001)
6831-6840.
[31] N. Azum, M.A. Rub, A.M. Asiri, Micellization and Interfacial Behavior of the
Sodium Salt of Ibuprofen-BRIJ-58 in Aqueous/Brine Solutions. J Sol. Chem.45
(2016) 791-803.
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[33] D.N. Rubingh, Solution Chemistry of Surfactants, Plenum, New York, 1979.
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[35] H. Maeda, A simple thermodynamic analysis of the stability of ionic/nonionic
mixed micelles. J. Coll. Interf. Sci. 172 (1995) 98-105.
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properties of alkanediyl-α,ω-bis(sodium N-acyl-β-alaninate) gemini surfactants. J.
Colloid Interf. Sci.262 (2003) 516-524.

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[37] J.H. de Boer, The Dynamic Character of Adsorption, Oxford University Press,
Oxford, 1953.
[38] R. Miller, V. Dutschk, V.B. Fainerman, Influence of molecular processes at liquid
interfaces on dynamic surface tensions and wetting kinetics. J. Adhesion 80 (2004)
549-561.
[39] R. Miller, D. Grigoriev, J. Krägel, A.V. Makievski, V.B. Fainerman, V.I.
Kovalchuk, L. Liggieri, F. Ravera, M. Ferrari, E. Santini, G. Loglio, V. Dutschk,
T. Karapantsios, Project proposal for the investigation of particle-stabilised
emulsions and foams by microgravity experiments. Microgravity Sci. Technology
18 (2006) 104-107.
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amphiphilic drug ibuprofen and surfactant mixture in the presence of electrolyte.
Colloids and surfaces B: Biointerfaces 121 (2014) 158‒164.
[41] N. Azum, M.A. Rub, A.M. Asiri, Experimental and theoretical approach to mixed
surfactant system of cationic gemini surfactant with nonionic surfactant in aqueous
medium. J. Mol. Liqs. 196 (2014) 14-20.
[42] N. Azum, M.A. Rub, A.M. Asiri, Micellization and interfacial behavior of binary
and ternary mixtures in aqueous medium. J Mol. Liqs. 216 (2016) 94–98.
[43] N. Azum, M.A. Rub, A.M. Asiri, Interaction of triblock copolymer with cationic
gemini and conventional surfactants: A physicochemical study. J Disp. Sci.
Tech. (2017) doi: 10.1080/01932691.2017.1283510.
[44] G. Sugihara, A.M. Miyazono, S. Nagadome, T. Oida, Y. Hayashi, J.S. Ko,
Adsorption and micelle formation of mixed surfactant systems in water ii: a
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(2003) 449-461.
[45] D.G. Hall, Electrostatic effects in dilute solutions containing charged colloidal
entities. J. Chem. Soc., Faraday Trans.87 (1991) 3529-3535.
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phenomenon of promazine hydrochloride under the influence of sodium
cholate/ Sodium deoxycholate in aqueous medium. J. Disp. Sci. Tech.37 (2016)
450-463.
[48] M.A. Rub, F. Khan, M.S. Sheikh, N. Azum, A.M. Asiri, Tensiometric,
fluorescence and 1H NMR study of mixed micellization of non-steroidal anti-
inflammatory drug sodium salt of ibuprofen in the presence of non-ionic surfactant
in aqueous/urea solutions. J. Chem. Therm. 96 (2016) 196-207.
[49] M.A. Rub, N. Azum, A.M. Asiri, M.E.M. Zayed, A.O. Al-Youbi, Solution
properties of phenothiazine drug promazine hydrochloride with cationic
hydrotropes in aqueous/electrolyte solution at different temperature. J Phys. Org.
Chem. 29 (2016) 476-489.
[50] N. Azum, M.A. Rub, A.M. Asiri, A.O. Al-Youbi, Thermodynamic properties of
sodium 2-(4-isobutylphenyl) propionate (sodium salt of ibuprofen) in aqueous/urea
micellar solutions at 298.15 K. Russ. J. Phys. Chem. A 91 (2017) 685-691.
[51] N. Azum, M.A. Rub, A.M. Asiri, Self-assocaition and microenvironmental
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[52] M.A. Rub, N. Azum, A.M. Asiri, Interaction of cationic amphiphilic drug
nortriptyline hydrochloride with TX-100 in aqueous and urea solutions and the
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(2016) 595-603.

25 | P a g e
Scheme 1: The aggregates structures of amphiphiles, predicted from packing parameter.

26 | P a g e
 S

Cl N
CH3
N HCL
CH3
(a)

O H
O
H3C n
H3C
H3C H3C CH3
TX-100, n = 9-10
TX-114, n = 7 or 8
(b)

Fig. 1. Chemical structure of (a) Chlorpromazine hydrochloride (CPZ), (b) Triton X.

27 | P a g e
 75
0.0
70 0.1
(a) 0.3
65 0.5
0.7
60 0.9
1.0
55

-1
 mNm
50

45

40

35

30

25
-5.5 -5.0 -4.5 -4.0 -3.5 -3.0 -2.5 -2.0

-3
log [ST] /mol dm

75
0.0
70 0.1
0.3
65 (b) 0.5
0.7
60 0.9
1.0
55
-1

50
 mNm

45

40

35

30

25
-5.0 -4.5 -4.0 -3.5 -3.0 -2.5 -2.0
-3
log [ST] /mol dm

Fig. 2. Plots of surface tension (γ) vs. the logarithm of total amphiphile concentration (ST)
of binary mixtures at various mole fractions of CPZ (a) CPZ+TX-100 (b) CPZ+TX-114
at 298 K.

28 | P a g e
 2.4
cmcexp
cmcideal
2.0 (a)

-3
1.6

cmc 10 / mol dm 1.2

3

0.8

0.4

0.0
0.0 0.2 0.4 0.6 0.8 1.0

CPZ

2.4
cmcexp
2.0 cmcideal
(b)
1.6
-3
cmc 10 / mol dm

1.2
3

0.8

0.4

0.0
0.0 0.2 0.4 0.6 0.8 1.0

CPZ

Fig. 3. Plots of experimental cmc (cmcexp) and ideal cmc (cmcideal) versus mole fraction of
CPZ (αCPZ) for (a) CPZ+TX-100 and (b) CPZ+TX-114.

29 | P a g e
 3500

TX-100
3000

K
2500

2000
Intensity A

1500

1000

500

400 450 500 550 600

Wavelength (nm)

4000
TX-114
3500

3000 K

2500

A
Intensity

2000

1500

1000

500

400 450 500 550 600

Wavelength (nm)

Fig. 4. Fluorescence spectra of pure CPZ at λex = 315 nm in the presence of increasing
[TX-100/TX-114] concentration from 0.025 to 0.25 mM.

30 | P a g e
 3600 TX-100
TX-114
3400

3200

3000

2800
Intensity
2600

2400

2200

2000

1800

1600
0.00 0.05 0.10 0.15 0.20 0.25

[TX-100/TX-114] /mM

Fig. 5. Plots of fluorescence intensities for CPZ as a function of surfactants

concentrations at λex = 315 nm.

31 | P a g e
 2.5
TX-100 2.30

1
2.25
2.0
2.20 11

Absorbance
2.15

1.5
2.10

Intensity 2.05

1.0 2.00
295 300 305 310 315 320

Wavelength (nm)

0.5

0.0
280 300 320 340 360 380 400 420 440

Wavelength (nm)

2.5
TX-114
2.4

2.0 2.3

2.2 11
Absorbance

2.1
1.5
Intensity

2.0

1.9
1.0 290 295 300 305 310 315 320 325

Wavelength (nm)

0.5

0.0
280 300 320 340 360 380 400

Wavelength (nm)

Fig. 6. Electronic absorption spectra of pure CPZ in the presence of increasing the
concentration of TX-100/TX-114.

32 | P a g e
 Table 1. Interfacial parameters for CPZ+TX-100/TX-114 mixtures at 298.15 K.

αCPZ Z1 106 Γmax Amin Aideal pC20 γcmc π V0 lc P

(mol m–2) (nm2) (nm2) (mN m–1) (mN m–1)
CPZ+TX-100
0 – 2.423 0.685 4.98 29.64 40.36 1776 41.86 0.62
0.1 0.41 1.651 1.005 0.831 4.81 31.35 38.65 2691 63.28 0.42
0.3 0.43 1.630 1.018 0.839 4.66 29.64 40.36 2691 63.28 0.42
0.5 0.45 1.761 0.942 0.844 4.44 30.01 39.99 2691 63.28 0.45
0.7 0.47 1.817 0.913 0.852 4.34 32.01 37.99 2691 63.28 0.46
0.9 0.51 2.108 0.787 0.865 3.74 34.27 35.73 2691 63.28 0.54
1 – 1.593 1.042 2.13 45.32 24.68 915 21.70 0.40
CPZ+TX-114
0 – 3.203 0.518 4.99 28.12 41.88 1561 36.82 0.81
0.1 0.42 1.980 0.838 0.732 4.83 28.09 41.91 2475 58.24 0.51
0.3 0.44 2.146 0.773 0.744 4.60 28.33 41.67 2475 58.24 0.55
0.5 0.45 2.164 0.767 0.751 4.49 29.03 40.97 2475 58.24 0.55
0.7 0.47 2.175 0.763 0.762 4.39 29.05 40.95 2475 58.24 0.56
0.9 0.51 2.238 0.741 0.782 3.80 31.11 38.89 2475 58.24 0.57
1 – 1.593 1.042 2.13 45.32 24.68 915 21.70 0.40

33 | P a g e
Table 2. Different physicochemical parameters for CPZ+TX-100/TX-114 mixtures at
298.15 K.

αCPZ 103 cmcexp 103 cmcideal X1 Xideal –β f1 f2

(mol dm-3) (mol dm-3)
CPZ + TX-100
0.0 0.282
0.1 0.234 0.313 0.15 0.002 6.27 0.011 0.868
0.3 0.332 0.399 0.13 0.008 3.80 0.055 0.941
0.5 0.440 0.553 0.16 0.019 3.33 0.095 0.918
0.7 0.605 0.899 0.23 0.043 3.47 0.127 0.832
0.9 1.210 2.398 0.35 0.149 3.64 0.214 0.639
1.0 14.500
CPZ + TX-114
0.0 0.263
0.1 0.257 0.292 0.09 0.002 4.72 0.019 0.963
0.3 0.302 0.373 0.14 0.008 4.12 0.046 0.926
0.5 0.410 0.516 0.16 0.018 3.37 0.091 0.921
0.7 0.569 0.841 0.23 0.040 3.51 0.121 0.835
0.9 1.360 2.259 0.32 0.141 2.89 0.264 0.742
1 14.50

34 | P a g e
Table 3. Thermodynamic parameters CPZ+TX-100/TX-114 mixtures at 298.15 K.

𝑜 𝑜 𝑜
αCPZ –B0 B1 –∆𝐺𝑚𝑖𝑐 –∆𝐺𝑎𝑑 Gmin –∆𝐺𝑀𝑎𝑒𝑑𝑎 –Δ𝐺𝑒𝑥
1
(kJmol- ) (kJmol- 1
) (kJmol-1) (kJmol-1) (kJmol-1)
CPZ+TX-100
0 30.20 46.85 12.23
46.92a
0.1 12.19 1.68 30.66 54.06 18.97 29.24 1.98
0.3 12.19 4.15 29.79 54.55 18.18 28.77 1.04
0.5 12.19 4.62 29.09 51.79 17.03 28.17 1.11
0.7 12.19 4.48 28.31 49.21 17.61 27.21 1.52
0.9 12.19 4.31 26.60 43.54 16.25 25.37 2.05
1 20.44 35.93 28.44
a
36.04
CPZ+TX-114
0 30.37 43.45 8.77
40.86a
0.1 12.26 3.30 30.43 51.58 14.18 29.57 0.95
0.3 12.26 3.90 30.03 49.44 13.19 28.89 1.20
0.5 12.26 4.66 29.27 48.20 13.41 28.38 1.10
0.7 12.26 4.51 28.46 47.28 13.35 27.42 1.52
0.9 12.26 5.13 26.30 43.67 13.90 25.57 1.56
1 20.44 35.93 28.44
36.04a
a
From de Boer Eq. (22)

35 | P a g e