Colloids and Surfaces A: Physicochem. Eng.

Aspects 498 (2016) 206–217

Contents lists available at ScienceDirect

Colloids and Surfaces A: Physicochemical and

Engineering Aspects
journal homepage: www.elsevier.com/locate/colsurfa

Effect of surfactant head group on micellization and morphological

transitions in drug-Surfactant catanionic mixture: A multi-technique
approach
Rajni Vashishat, Shruti Chabba, Rakesh Kumar Mahajan ∗
Department of Chemistry, UGC-Centre for Advanced Studies, Guru Nanak Dev University, Amritsar-143005, India

h i g h l i g h t s g r a p h i c a l a b s t r a c t

• Synergistic interactions between

Tetracaine and anionic surfactants.
• Solubilization of Tetracaine in
micelles core.
• Morphological transitions in
TC + SDBS mixed mixtures.
• 1:1 catanionic complex formation of
TC + SLS/SDBS mixtures.

a r t i c l e i n f o a b s t r a c t

Article history: This work aims to explore the various interactions prevailing in catanionic mixtures of cationic
Received 27 January 2016 amphiphilic drug tetracaine hydrochloride (TC) and anionic surfactants viz. sodium lauroyl sarcosinate
Received in revised form 18 March 2016 (SLS) and sodium dodecylbenzenesulfonate (SDBS). The synergistic interactions in terms of micellar,
Accepted 23 March 2016
interfacial and thermodynamic parameters in binary mixtures of TC and SLS/SDBS have been investi-
Available online 24 March 2016
gated by employing surface tension measurement. The microenvironment of TC in micellar media, the
binding constant and the stoichiometry of catanionic complexes have been examined from steady state
Keywords:
fluorescence, three dimensional (3D) fluorescence and UV–vis spectroscopy. The thermodynamic heat
Tetracaine hydrochloride
3D fluorescence
changes were also investigated by using isothermal titration calorimetry (ITC). The more exothermic heat
Binding constant changes were observed in TC + SDBS in comparison to TC + SLS mixture owing to the presence of strong
Job’s plot electrostatic, hydrophobic and ␲-␲ stacking interactions in former. Furthermore the effect of different
Morphological transitions head groups on the morphology and hydrodynamic diameter (Dh ) were explored using, dynamic light
scattering (DLS) and transmission electron microscopy (TEM) techniques. We observed the morphologi-
cal transition such as vesicle formation in TC-SDBS mixtures at different mole fractions of TC whereas in
TC-SLS the Dh values first increases with increasing mole fraction of TC and then decreases which signifies
only the changes in micellar aggregates and no transition to larger aggregates. This work speculate the

∗ Corresponding author.
E-mail address: rakesh [email protected] (R.K. Mahajan).

http://dx.doi.org/10.1016/j.colsurfa.2016.03.058
0927-7757/© 2016 Elsevier B.V. All rights reserved.
 R. Vashishat et al. / Colloids and Surfaces A: Physicochem. Eng. Aspects 498 (2016) 206–217 207

potential of TC and SLS/SDBS mixtures which can be used as drug carriers to alter physicochemical and
pharmacokinetic characteristics of drugs.
© 2016 Elsevier B.V. All rights reserved.

1. Introduction of the mixtures. Both, SLS and SDBS are superior to conventional
surfactants due to their attractive applications in cosmetics and
Catanionic systems have aroused much attention over a past pharmaceutical formulations. SLS, amino acid based anionic sur-
decade as they offer great potential in delivering biological macro- factant is a derivative of sarcosinate and offers many biological
molecules, drugs, and cosmetics across the cell membrane. They as well as industrial uses [18–20]. SDBS also possess numerous
have also been used as model system for biological membranes applications like, it act as a suitable template for the synthesis of
[1,2]. The catanionic mixtures comprising oppositely charged nanoparticles and nanotubes, host for entrapping environmental
amphiphiles formed by spontaneous mixing can produce a distinct hazardous substances, bio compatible as it desorbs many harm-
variety of aggregate microstructures, such as spherical and rod- ful organic compounds from soil and improves the efficiency of
like micelles, vesicles, lamellar phases, and even precipitates [3–6]. soil [21–24]. These surfactants are mild, less irritating to skin and
The addition of oppositely charged amphiphiles reduces the sur- also have antimicrobial activities so they will enhance the penetra-
face charge density of the mixed micelles and hence minimizes tion of drugs through skin. Thus the study of interfacial properties
the charge repulsions which leads to the formation of complex of SLS/SDBS and their interactions with bio-active compounds
aggregates [7]. like drugs, proteins and polymers are very important to study to
Among the various types of aggregate assemblies, catanionic improve their uses in industries.
vesicles are more popular as they show distinct advantages over The amphiphilic drug TC is a local anaesthetic and has the ability
phospholipid vesicles due to their non-toxicity, higher stability, to bind with cellular membrane where it gets incorporated into the
longer shelf life and cheaper raw materials [8–10]. A dozens hydrophobic environment of the cell membrane and can displace
of reports regarding mixing of cationic and anionic amphiphiles the ions from water − membrane interface [25]. Thus the knowl-
have been reviewed in the literature [11–17]. In this regard, edge of interactions between TC and SLS/SDBS mixtures would
Abbott et al. have discussed the bilayer formation on mixing assist in knowing the mechanism through which TC gets incor-
cationic bolaform surfactants with either sodium dodecylsulfate or porated into hydrophobic environment of the biomembranes. To
sodium tetradecylsulfate in aqueous solutions by using small angle the best of our knowledge there is no report that explains the
neutron scattering measurements [11]. The catanionic vesicle for- micellization of TC drug with SLS and SDBS surfactants along with
mation in twin tailed surfactants, didodecyldimethylammonium spectroscopic and thermodynamic measurements. Significantly,
bromide (DDAB)/sodium bis(2-ethylhexyl) phosphate (NaDEHP) this study would be helpful in evaluating the effect of negatively
by regulating the DDAB/NaDEHP surfactant molar ratio have been charged different head groups of conventional surfactants on micel-
investigated by Luan and co-workers [12]. The microstructural lar structural change in TC-SLS/SDBS system.
transitions from prolate micelles to oblate micelles on adding
anionic bile salt sodium deoxycholate (NaDC) in cationic surfac-
tant cetylpyridinium chloride (CPC) have been reported by Hassan 2. Experimental
and co-workers [13]. In another study they have also reported the
microstructural changes in tetradecyltrimethylammonium bro- 2.1. Materials
mide (TTAB) micelles induced by the addition of sodium laurate
(SL) [14]. Bergstrom et al. have suitably studied the transitions The amphiphilic drug tetracaine hydrochloride (TC,
of micellar aggregates into unilamellar vesicles upon dilution in purity ≥ 99%) sodium dodecylbenzenesulfonate (SDBS,
the catanionic mixture of sodium dodecyl sulfate (SDS) and dode- purity ≥ 99%) sodium lauroyl sarcosinate (SLS, purity ≥ 99%)
cyltrimethylammonium bromide (DTAB) [15]. and sodium Chloride (NaCl, purity ≥ 99%) were purchased from
Mahajan et al. have studied the interactions between cationic Sigma Aldrich and used as received without further purification.
drug, trifluoperazine dihydrochloride (TFP) and ionic surfactants Double distilled water having a specific conductivity in the range
such as sodium dodecylsulphate (SDS), dioctylsulphosuccinate of 1–2 ␮S was used in all the measurements. The solutions were
sodium salt (AOT), dodecyltrimethylammonium bromide (DTAB) prepared by dissolving accurately weighed quantities of differ-
and didodecyldimethylammonium bromide (DDAB) and the oppo- ent substances by using analytical balance with a precision of
sitely charged drug-surfactant mixtures were found to be highly ±0.0001 g. The chemical structures of the used chemicals are given
synergistic [16]. In another study, they have investigated the syn- in Fig. S1 of supporting information.
ergistic interactions and micellar transitions in catanionic mixture
of ibuprofen − ionic liquid (1-dodecyl-3-methylimidazolium chlo-
ride) in aqueous medium [17]. 2.2. Methods
Thus in continuation to our previous work regarding drug-
surfactant mixtures we have investigated the mixture comprising 2.2.1. Surface tension measurements
cationic amphiphilic drug tetracaine hydrochloride (TC) and The surface tension (␥) measurements were carried out using
anionic surfactants (sodium lauroyl sarcosinate, SLS and sodium a Du Nouy ring Tensiometer (Kruss Easy Dyne Tensiometer) from
dodecylbenzenesulfonate, SDBS) possessing different head groups. Kruss Gmbh (Hamburg, Germany) equipped with thermostat using
So far, most of the published reports about catanionic mixtures a platinum ring at 298.15 ± 0.1 K. The plantinum ring prior to mea-
are focussed on the mixing of oppositely charged surfactants surements was washed thoroughly with warm double distilled
(cationic and anionic) and catanionic drug-surfactant mixtures water. The ␥ value of doubly distilled water 72 mN m−1 was used
remains unexplored. Moreover we were also interested in study- to calibrate the instrument. The ␥ values of pure TC, SLS, SDBS and
ing the effect of head groups of surfactants on the morphology their binary mixtures (TC + SLS/SDBS) were measured by successive
addition of stock solutions (at 10 times their cmc). The reproducibil-
208 R. Vashishat et al. / Colloids and Surfaces A: Physicochem. Eng. Aspects 498 (2016) 206–217

ity in the measurements of ␥ values with tensiometer is ± 0.15 mN Table 1

Micellar parameters: experimental cmc, ideal cmc (cmc*), micellar mole fraction
m−1 .
(X1 m ), ideal mole fraction (Xideal ) and micellar interaction parameter (␤m ) of binary
mixtures of tetracaine hydrochloride (TC) with anionic surfactants (SLS and SDBS).
2.2.2. Fluorescence measurements
␣TC cmca (mM) cmc* (mM) X1 m Xideal ˇm
The steady state fluorescence measurements were performed
on Hitachi F-4600 fluorescence spectrophotometer using a 10 mm TC + SLS
path length quartz cuvette at 298.15 ± 0.1 K. The titrations were 0.0 14.0
0.1 3.2 15.3 0.34 0.02 −10.15 ± 0.11
performed by adding concentrated stock solutions of SLS and SDBS
0.3 2.2 18.6 0.40 0.07 −10.70 ± 0.09
directly into the quartz cuvette containing 2 mL of 0.05 mM TC 0.7 2.5 33.0 0.47 0.30 −10.87 ± 0.10
solution. The emission spectra of TC was recorded in the range of 0.9 3.9 54.0 0.52 0.61 −10.68 ± 0.12
320–500 nm wavelength by excitation at 310 nm. 1.0 79.2
TC + SDBS
The three dimensional (3D) fluorescence measurements were
0.0 1.82
also carried out for TC in the absence and in the presence of both 0.1 0.37 1.99 0.32 0.002 −14.12 ± 0.08
SLS and SDBS by scanning over an excitation wavelength from 0.3 0.11 2.55 0.39 0.010 −18.39 ± 0.09
200 to 450 nm at excitation sampling interval 5 nm and emission 0.7 2.61 5.70 0.31 0.050 −5.46 ± 0.07
wavelength from 200 to 600 nm at interval of 5 nm. The excitation 0.9 0.10 14.94 0.47 0.170 −21.45 ± 0.11

and emission band slits were fixed at 5 nm and scanning speed of

1200 nm/min was used for all measurements.
been provided in Fig. S2(a) and S2(b) of supporting information and
2.2.3. UV–vis measurements experimentally determined cmc values were found to be in good
The absorption spectra were recorded on a UV-1800 Shimadzu agreement with literature values [7,26,27]. The higher cmc of TC
UV–vis spectrophotometer with a quartz cuvette with a path length revealed the lesser extent of TC to form aggregates, whereas SLS and
of 1 cm. The absorbance of pure TC, SLS, SDBS and their aqueous SDBS have low cmc. Both SLS and SDBS have long alkyl chain with
mixtures at varying mole fractions of TC were recorded at 298.15 K same number of carbons but SDBS posses more hydrophobicity
in the range of 200–500 nm. owing to the presence of benzene ring which participates in charge
delocalization and effective in reducing the electrostatic repul-
2.2.4. Isothermal titration calorimetry (ITC) measurements sions among polar headgroup [28]. However in SLS the negative
Calorimetric titrations were performed by using a MicroCal charge remains concentrated on carbonyl group and less delocal-
IT200 microcalorimeter at 298.15 K. The sample cell was filled with ized which results in intermicellar repulsions. Fig. 1(a) and 1(b)
200 ␮L of a solution of 2 mM TC and the syringe was filled with shows the variation of surface tension as a function of total surfac-
40 ␮L of either SLS or SDBS and 2 ␮L aliquots were added into tant concentration for TC + SLS and TC + SDBS mixtures at various
cell. The parameters like time of addition and duration between ␣TC respectively. The cmc values of all the mixtures have been
each addition were monitored by the software provided with the presented in Table 1. It was observed that the ␥ values contin-
instrument ues to decrease with increase in concentration of mixtures before
reaching the critical micellar concentration, and become constant
2.2.5. Dynamic light scattering (DLS) measurements when cmc reached. The mixed micellization process is highly
DLS measurements were carried out to determine the parti- dependent on two important factors: (a) electrostatic interactions
cle size using Malvern NanoZS zeta-sizer equipped with 632.8 nm between oppositely charged head groups (b) hydrophobic interac-
He-Ne laser in backscattering mode at a scattering angle of 173◦ . tions among hydrophobic components. In our present study, both
The temperature 298.15 K was maintained by in-built temperature TC and SLS/SDBS bear opposite charge and thus favour the mixed
controller having an accuracy of ±0.1 K. All the samples prior to micellization. The increasing mole fraction of TC into SLS and SDBS
measurements were properly filtered from 0.2 ␮m filters to avoid reduces the cmc than pure amphiphiles due to presence of strong
interference from dust particles electrostatic interactions among oppositely charged head groups as
well as hydrophobic interactions between tails. The cmc values of
2.2.6. Transmission electron microscopy (TEM) TC + SLS/SDBS mixtures continues to decrease with increasing mole
TEM measurements were performed on JEM-2100 transmission fraction of TC but starts to increase in cationic rich region, which
electron microscope (TEM) at a working voltage of 200 kV without have been commonly observed in catanionic mixtures [29–31]. The
staining the sample. A drop of freshly prepared aqueous solution of somewhat different behavior have been observed at ␣TC = 0.9 in
TC-SDBS binary mixture was placed on a carbon coated copper grid TC + SDBS mixtures, where the cmc value again decreases which
(300 mesh), and the residual solution was blotted off. The samples can be ascribed to vesicle formation (discussed later) guided by
for TEM measurements were dried in air at room temperature for strong binding forces among oppositely charged molecules.
24 h before measurements
3.1.1. Micellar parameters
3. Results and discussion Next, the ideal or non-ideal nature of TC-SLS/SDBS mixtures
have been studied by using Clint’s Eq. (1), based on pseudo-phase
3.1. TC-SLS/SDBS interactions in mixed micelles model [32]
1 ˛1 (1 − ˛1 )
Tensiometry study have been used to investigate the interac- = + (1)
cmc ∗ cmc1 cmc2
tional behaviour of cationic drug tetracaine hydrochloride (TC) with
anionic surfactants, sodium lauroyl sarcosinate (SLS) and sodium where ␣1 represents the mole fraction of TC, cmc1 and cmc2 are
dodecylbenzenesulfonate (SDBS) at varying mole fractions of TC the experimental cmc values of pure TC and pure SLS/SDBS respec-
(␣TC ). The critical micelle concentration (cmc) values of pure TC, tively in the bulk whereas cmc* is the ideal cmc. The data regarding
SLS and SDBS have been computed from the breakpoints in the the micellar parameters have been provided in Table 1 and it has
plots of surface tension (␥) vs. log of total surfactant concentration been found that the experimentally determined cmc values of TC
and worked out to be 79.18 mM, 14 mM and 1.8 mM respectively. + SLS/SDBS mixed micellar mixtures deviate from ideal cmc values
The representative tensiometric profile of pure amphiphiles have are much lower in magnitude which illustrate the non-ideal mixing
 R. Vashishat et al. / Colloids and Surfaces A: Physicochem. Eng. Aspects 498 (2016) 206–217 209

Fig. 1. Plots of surface tension () vs. the logarithm of total amphiphilic concentration (Ct ) of binary mixture of (a) TC + SLS and (b) TC + SDBS at various mole fractions of TC
(␣TC ).

between the components. The non-ideality of mixtures is also due be due to the reason that more TC molecules orient the bulkier
to strong attractive interactions present among molecules. Further, headgroups of SDBS molecules in such a array that they release the
to justify the presence of synergism in TC and SLS/SDBS mixtures TC molecules and reduces repulsive interactions there. Malik et al.
micellar mole fraction (X1 m ) and micellar interaction parameter [41] have reported the micellization and adsorption behaviour of
(␤m ) can be calculated (equation 2 and 3) on the basis of Rubingh’s the amphiphilic cationic drug promethazine hydrochloride (PMT)
theory [33]. There are many models which can be employed to and anionic bile salts mixtures and have explored the synergistic
determine micellar mole fractions and interaction parameter but interactions in the form of interaction parameters. Similarly Wajid
all the models give more or less similar trends in micellar mole et al. [34] have also studied the interactions between amphiphilic
fractions and interaction parameters. However, Rubingh’s model drug amitriptyline hydrochloride (AMT) and three anionic gemini
has an advantage: it is much simpler than the other models and is surfactants. They have investigated the effect of hydrophobic tail of
still widely used [34,35]. surfactants on the mixed micellization of drug-surfactant mixtures.
  The interactions in cationic drug and anionic gemini surfactants
˛1 cmc12
X1m ln X m cmc1
were favoured by the presence of oppositely charged moieties of
1
 2  (1−˛  =1 (2) both.
1 )cmc12
1 − X1m ln (1−X1 )cmc2 The micellar mole fraction of mixed systems in ideal state (Xideal )
  have been computed by Motomura’s approximation [42] given by
cmc12 ˛1 Eq. (4)
ln cmc1 X m
ˇm = 
1
2 (3) ˛1 cmc2
1 − X1m X ideal = (4)
˛1 cmc2 + (1 − ˛1 ) cmc1
In Eqs. (2) and (3) cmc12 represents the experimental cmc value From Table 1, the Xideal values were found to be less than X1 m for
of TC + SLS/SDBS binary mixtures, X1 m is the micellar mole frac- most of the mixtures at all the mole fractions of TC, indicate that
tion of TC in mixed micelles which is then substituted into Eq. the formed mixed micelles were rich in TC component. An opposite
(3) to determine ␤m , an indicator of the extent of interactions trend at cationic rich region in TC + SLS noticed which justify that
between two different molecules in mixed micelles. As clear from at higher concentration of TC, repulsion occurs due to the presence
the data (Table 1), the negative magnitude of ␤m in TC + SLS/SDBS of greater component of SLS molecules.
mixtures at all mole fractions of TC indicates the strong attrac-
tive interactions and lesser repulsive interactions exist among 3.1.2. Interfacial parameters
oppositely charged molecules. This suggest that mixed micelles for- The surface properties and surface adsorption behavior of TC +
mation between unlike molecules is more favoured rather than self SLS/SDBS aqueous mixtures have been computed employing sur-
assembly of pure amphiphiles. The high negative magnitude of ␤m face tension technique. The maximum surface excess concentration
indicates the presence of strong synergistic interactions in mix- (␶max ), the measure of adsorption effectiveness of amphiphiles at
tures. On comparing ␤m values of TC + SDBS mixtures with TC + air-water interface and minimum area per molecule (Amin ) have
SLS mixtures values, the direct evidence comes for the more strong been described in Annexure S1. The  max and Amin value for pure
attractive interactions between TC and SDBS rather than TC and SLS. SLS and SDBS have been provided in Table 2. The  max and Amin
This might be due to the presence of additional ␲-␲ stacking forces values were calculated by using Gibbs equation but Thomas et al.
in TC + SDBS mixtures in addition to various interactions such as reported that the applicability of Gibbs equation is limited due to
electrostatic interactions between oppositely charged molecules, finite width of micellization [43]. The detailed analysis of state of
hydrophobic forces, ion-dipole interactions and hydrogen bonding. adsorption is beyond this work so still this Gibbs equation is valid
There is no regular trend in ␤m values observed in TC + SLS mixtures for the determination of  max and Amin values [44,45]. The higher
whereas in TC + SDBS mixtures ␤m values first increases in anionic value of Amin and lower value of  max were found to be in pure SLS
rich region followed by decrease in magnitude when concentration and SDBS as compared to TC, due to larger hydrophiphilic heads and
exceeds equimolarity which can be attributed to the steric hin- hydrophobic tails which offers looser packing at air-water inter-
drance offered by more TC molecules as earlier reported in many face. However, the addition of TC molecules increases the packing
catanionic mixtures [36–40]. But at ␣TC = 0.9 in case of TC + SDBS, density and decreases Amin but as we go from anionic rich region to
the highest ␤m value were found to be present when which might cationic rich region Amin increases again. This signifies that catan-
210 R. Vashishat et al. / Colloids and Surfaces A: Physicochem. Eng. Aspects 498 (2016) 206–217

Table 2 Table 3
Interfacial parameters: surface tension at cmc ( cmc ), surface pressure at cmc (␲cmc ), Thermodynamic parameters: standard free energy of micellization (G◦ m ), stan-
surface excess ( max ) and minimum area per molecule (Amin ) of binary mixtures of dard free energy of adsorption (G◦ ad ), surface free energy (Gs min ), excess free
tetracaine hydrochloride (TC) with anionic surfactants (SLS and SDBS). energy (Gex ) of binary mixtures of tetracaine hydrochloride (TC) with anionic
surfactants (SLS and SDBS).
␣TC  cmc (mN m−1 ) ˘ cmc (mN m−1 ) 106  max (mol m−2 ) Amin (Å2 )
␣TC Go m (kJ mol-1 ) Go ad (kJ mol-1 ) Gs min (kJ mol-1 ) Gex (kJ mol-1 )
TC + SLS
TC + SLS
0.0 32.5 39.5 1.64 ± 0.02 101.24 ± 0.02
0.0 −20.53 ± 0.09 −44.62 ± 0.05 19.81 ± 0.09
0.1 26.6 45.3 1.75 ± 0.01 95.00 ± 0.02
0.1 −24.07 ± 0.10 −49.98 ± 0.05 15.25 ± 0.12 −5.63 ± 0.12
0.3 26.4 45.5 1.84 ± 0.03 90.27 ± 0.04
0.3 −24.98 ± 0.08 −49.73 ± 0.04 14.38 ± 0.08 −6.35 ± 0.11
0.7 25.1 46.8 2.82 ± 0.05 72.75 ± 0.04
0.7 −24.70 ± 0.05 −45.27 ± 0.06 11.00 ± 0.09 −3.43 ± 0.09
0.9 27.4 44.6 2.22 ± 0.05 74.74 ± 0.03
0.9 −23.61 ± 0.11 −43.69 ± 0.08 12.35 ± 0.10 −6.57 ± 0.09
1.0 37.14 34.9 1.98 ± 0.04 83.85 ± 0.05
1.0 −16.24 ± 0.08 −33.87 ± 0.10 18.76 ± 0.09
TC + SDBS
0.0 33.12 38.9 1.29 ± 0.01 128.71 ± 0.01 TC + SDBS
0.1 27.9 44.1 1.31 ± 0.02 127.15 ± 0.02 0.0 −25.60 ± 0.13 −55.76 ± 0.14 16.12 ± 0.14
0.3 28.7 43.3 2.01 ± 0.03 82.51 ± 0.04 0.1 −29.43 ± 0.10 −63.09 ± 0.12 21.37 ± 0.15 −12.82 ± 0.09
0.7 28.6 43.8 2.59 ± 0.03 64.16 ± 0.03 0.3 −32.43 ± 0.09 −53.97 ± 0.10 14.26 ± 0.12 −10.87 ± 0.11
0.9 28.0 44.0 1.74 ± 0.05 95.56 ± 0.04 0.7 −24.60 ± 0.09 −41.35 ± 0.11 11.06 ± 0.11 −2.89 ± 0.06
0.9 −32.02 ± 0.08 −57.30 ± 0.10 16.12 ± 0.09 −12.65 ± 0.05

ionic mixtures are closed packed at interface and are expected to

be more hydrophobic than individual components. Thus from all the micellization parameters, interfacial parame-
Another important parameter is surface pressure (␲cmc ) at cmc ters and thermodynamic parameters it has been confirmed that the
which measures the effectiveness of the amphiphilic molecules catanionic mixture of TC with SLS and SDBS exhibits higher surface
to lower surface tension of solvent (Annexure S1 of supporting properties which might prove beneficial in industries.
information). It signifies the maximum reduction of surface ten-
sion caused by dissolution of amphiphiles. From the ␲cmc values 3.2. TC-SLS/SDBS catanionic complex formation: spectroscopy
given in Table 2, the catanionic mixtures were proved to possess measurements
better surface activity than individual components and are more
efficient in reducing the surface tension of water. To have the deeper insight into the catanionic complex forma-
tion between TC and SLS/SDBS, the spectroscopic measurements
3.1.3. Thermodynamic parameters were further carried out. The steady state fluorescence mea-
Next, it is important to resolve the effect of TC on micellization surements decipher the detailed picture of binding interactions
and adsorption in the mixture which has been done on account between TC and surfactants and also give clue about the local envi-
of thermodynamic parameters. The standard free energy of micel- ronment of drug in micellar media which is an important aspect.
lization (G◦ m ) for pure components and their mixtures have been Next, the UV–vis spectroscopy has been employed to confirm the
counted using Eq. (5) and further used in Eq. (6) to evaluate standard TC-SLS/SDBS catanionic complex formation and also their stoi-
free energy of adsorption (G◦ ads ) chometry by continuous variation method (Job’s plot).

o
Gm = RT ln Xcmc (5) 3.2.1. Fluorescence spectroscopy
o
 o
  cmc  The chemical structure of TC contains tertiary amine and also
Gads = Gm − (6) secondary amine linked to phenyl ring, latter is responsible for
max
its rich fluorescence activity but in cases where pH > 4, emission
where Xcmc is the cmc in mole fraction units. The G◦ ads val- also occur at the cost of intramolecular charge transfer state where
ues indicates that work has to be done to transfer surfactants transfer of electrons takes place from N-lone pair of secondary
in monomeric form at surface to micellar state through aqueous amine (electron donor) to either ␲-orbitals of benzene ring or car-
medium. There are number of forces such as electrostatic attraction, bonyl group (electron acceptor) [40]. The fluorescence emission
covalent bonding, hydrogen bonding and hydrophobic interaction spectra of TC molecules is known to be dependent on change in
which are involved in adsorption phenomenon. The sum of such its microenvironment. In aqueous environment it gives an intense
contributing forces is the driving force for the adsorption. The influ- peak at 370 nm when excited at 310 nm. Intially TC molecules were
ence of such forces is reviewed in term of standard free energy of highly ordered in aqueous environment due to interaction of dipole
adsorption. As per Table 3 data, both G◦ m and G◦ ads have neg- moment of water molecules with dipole moment of fluorophores.
ative values which implies that both micellization and adsorption The emission spectra of TC in the presence of SLS and SDBS have
processes are spontaneous and feasible but the more negative val- been shown in Fig. 2(a) and 2(b) respectively (inset shows varia-
ues of G◦ ads signifies that adsorption process is more spontaneous tion of fluorescence intensity with concentration of SLS and SDBS).
than micellization. The high negative values of G◦ m and G◦ ads It becomes clear from figures that with increasing concentration
for the TC-SLS/SDBS mixtures at different mole fractions confirms of SLS/SDBS in TC, the fluorescence intensity enhance with hyp-
their high stability Another important parameters are standard free sochromic shift, indicating the change in polarity of medium. The
energy at equilibrium (G◦ mim ) and excess free energy (Gex ) which hypsochromic shift for TC was from 370 nm to 361 nm in 28.8 mM
are calculated by using Eqs. (7) and (8) as follows (Table 3). SLS and from 370 nm to 362 nm in 5 mM SDBS suggesting that
s local environment around TC get perturbed in micellar media with
Gmin = Amin cmc NA (7)
low polarity. This fluorescence enhancement in micellar media
    was due to twisted intramolecular charge transfer state (TICT). So
Gex = X1m ln f1m + 1 − X1 m m
ln f2 RT (8)
on excitation, TC molecules reaches to excited state, the excited
The Gs min values were found to be high for catanionic mixtures state of TC decay due to twisting of the aniline group around the
which indicates the more synergism in mixtures and they also pos- N-phenyl bond towards TICT state which increases the charge sep-
sess surface activity. The higher stability of the mixtures have been aration between excited state and ground state so increasing the
confirmed from negative values of Gex . radiative rate and decreasing the rotational freedom [46]. Intially
 R. Vashishat et al. / Colloids and Surfaces A: Physicochem. Eng. Aspects 498 (2016) 206–217 211

5500
3000
2500
5000 (a) 5000
cmc (b) 2500

4500 4000 2000 cmc

Fluorescence Intensity

Fluorescence Intensity
4000 3000 2000 1500
Fluorescence Intensity

Fluorescence Intensity
1000
3500 2000
500
3000 1000
cac
1500
0
0.000 0.001 0.002 0.003 0.004 0.005
0
2500 0.00 0.01 0.02 0.03 CSDBS/ mol dm-3
CSLS/ mol dm-3 1000
2000

1500 CSLS CSDBS

500
1000
500
0
0
320 340 360 380 400 420 440 320 340 360 380 400 420 440
Wavelength (nm) Wavelength (nm)

0.05

(c) TC + SLS
TC + SDBS
0.04

0.03
1/I-Io

0.02

0.01

0.00
0 2000 4000 6000 8000 10000 12000 14000 16000
-1 3
1/Ct mol dm

Fig. 2. Fluorescence emission spectra of TC (0.05 mM) (a) in the presence of increasing concentration of SLS and (b) in the presence of increasing concentration of SDBS. (Inset
of each figure shows the variation of fluorescence intensity vs. Surfactant concentration). 2(c) Benesi-Hildebrand plot for binding constant determination using changes in
fluorescence emission spectra of TC (0.05 mM) in the presence of varying concentration of SLS and SDBS.

the increase in fluorescence intensity of TC was slow until criti- emitted light using the relationship. The fluorescence intensity was
cal aggregation concentration (cac) of surfactant reached. Once cac corrected using the following equation [49].
reached, the sharp increase in intensity has been observed with (Aex +Aem )
Icor = Iobs × e 2 (9)
remarkable change in max , indicating that TC molecules strongly
bind with micellar surface having low dielectric constant than where Icor and Iobs are the fluorescence intensity corrected and
water which eventually enhance the quantum yield of the fluo- observed, respectively; Aex and Aem are the absorbance of system
rophore [47]. Once the cmc of surfactant reached the fluorescence at excitation (310 nm) and emission wavelength (362 nm), respec-
intensity of TC gets saturated with constant ␭max . This constancy in tively. The B-H equation is given as Eq. (10).
␭max along with saturated intensity were attributed to solubilisa-
1 1 1
tion of TC molecules in the hydrophobic core of the micellar media = n + I − I◦ (10)
I − I◦ Ka (I1 − I ) [Surf ]
◦ 1
[48].
Further the quantitative evaluation of interactions in TC- where I = I − Io ; Io and I is the intensity of 0.05 mM aqueous TC
SLS/SDBS in terms of binding constant have been given by in the absence and presence of surfactants respectively, I1 is the
Benesi-Hildebrand (B-H) equation. As the UV–vis absorption of fluorescence intensity of TC-Surf complex, [Surf.] denotes the molar
the system at excitation wavelength (310 nm) and emission wave- concentration of the added surfactants (SLS and SDBS) and n is the
length (362 nm) are not very low so the inner filter effect cannot stoichiometry coefficient.
be neglected. Therefore, the fluorescence intensity was corrected As shown in Figs. 2(c), the double reciprocal B-H plots of 1/I − Io
further for absorption of exciting light and the re-absorption of versus 1/[Surf]n gives linear relationship when n = 1 and indicates
1:1 stoichiometry of these TC-SLS/SDBS catanionic complexes. The
binding constant (Ka ) is determined from the intercept to slope
212 R. Vashishat et al. / Colloids and Surfaces A: Physicochem. Eng. Aspects 498 (2016) 206–217

Table 4 (A) represents the difference among measured absorbance (Aexp )

Evaluated binding constant (Ka ), free energy change (G) and correlation coeffi-
and theoretical absorbance (Atheo ) is given by following equation
cients (Rc ) for TC-SLS and TC-SDBS complex from fluorescence technique.

System Ka ( × 103 M−1 ) G (kJ mol−1 ) Rc A = Aexp − Atheo (12)

TC+SLS 0.26 ± 0.07 −13.80 ± 0.13 0.9974
The equations employed to calculate Aexp and Atheo are given
TC+SDBS 2.98 ± 0.06 −19.83 ± 0.1 0.9982
in Annexure S1 of supporting information. The plot of corrected
absorbance (A) versus the volume fraction of surfactant solution
gives either minima or maxima which corresponds to the stoi-
ratio of B-H plots and is given in Table 4. Both the SLS and SDBS
chiometry ratio of drug-surfactant complex. As shown in Fig. 4,
interact with TC and exist in equilibrium state as follows:
the presence of minima for D-S complexes at XS = 0.5 implies 1:1
Tetracaine hydrochloride (TC) + Surfactants (Surf) ↔ TC:Surf
stoichiometry.
Ka = [TC−Surf ]
[TC][Surf ]
Further the free energy change (G)for TC-Surf complexes can
be obtained by the use of Ka values according the equation as: 3.3. Isothermal titration calorimetry

G = −RT ln Ka (11) Microcalorimetry is the most sensitive and sophisticated which

measures the enthalpy changes of a reacting system when reac-
The G values have also been given in Table 4 where the negative tant is injected into the cell. It also offers the information regarding
values of G indicates the feasibility of the catanionic complex for- various types of interactions such as electrostatic, hydrophobic
mation. Both the Ka and G are higher in magnitude in TC-SDBS and hydrogen bonding which are present in reacting system [51].
mixture as compared to TC-SLS system, indicates the greater feasi- Here, ITC measurements were performed to explore the interac-
bility and stability of TC-SDBS catanionic complex due to stronger tions present in catanionic mixture of surfactants having anionic
electrostatic, hydrophobic as well as ␲-␲ stacking interactions. head groups and TC. Fig. 5(a) and 5(b) shows the enthalpy changes
Such ␲-␲ stacking interactions are absent in TC–SLS mixtures. for the titration of micellar SLS (200 mM) and SDBS (50 mM) to
the both water and TC (2 mM) and raw profiles have been given
3.2.2. Three dimensional (3D) fluorescence spectroscopy as Fig. S3 (a) and S3 (b). The enthalpogram of SLS and SDBS into
The 3D fluorescence spectroscopy has become leading tech- water shows that the injection of micelles into cell first dissociate
nique in recent years as it provide precise information about the the micelles into monomers, after that formation of micelles takes
conformational changes in the fluorophore by changing excitation place followed by further dilution of micelles without dissociation.
and emission wavelength simultaneously [50]. In the present study, So the heat from a number of factors such as dissociation of micelles
the 3D fluorescence spectrum of TC drug in the absence and pres- to monomers, hydration of monomers, dilution effect and binding
ence of SLS and SDBS have been provided in Figs. 3(a) to 3(d). of surfactants with drug molecules contribute to the total overall
The maximum emission wavelength and the fluorescence intensity enthalpy change which is measured by ITC [52].
of TC is greatly associated with the microenvironment’s polarity.
Three peaks of pure TC located at ␭ex /␭em of 230/370, 283/370 and 3.3.1. Enthalpy changes for TC-SLS interactions
325/370 can be observed in Fig. 3(a) and the blue shift is observed In the absence of TC the enthalpy change associated with each
in all three peaks of TC in the presence of SLS and SDBS both. In injection was exothermic for the first few injections then decreased
the presence of 3.9 mM SLS (Fig. 3(b), near cac) the location of and finally became endothermic for the later injections. In the pres-
peaks changed with enhancement in fluorescence intensity. How- ence of drug the enthalpogram of SLS titration into TC was divided
ever the large hypsochromic shift conjointly with the fluorescence into three regions. In the first region marked as I where the concen-
enhancement. Similar results were seen in TC − SDBS mixture tration of SLS was lower than cac (< 4.2 mM) the high exothermicity
in the presence of 1.7 mM SDBS with additional peaks located at for the first few injections were attributed to the presence of
␭ex /␭em of 242/287 and 261/287 due to complexation between TC strong electrostatic interactions between oppositely charged SLS
and SDBS (Fig. 3d, near cmc). These results also support the com- monomers and TC molecules. The cationic aliphatic amine group
plex formation in TC-SLS/SDBS and also revealed the changes in of TC interact electrostatically with anionic carboxylate group of
TC microenvironment in micellar media. The details of the peak SLS and favours complex formation. It has been well established
locations have been provided in Table S1. that electrostatic binding is more prevalent driving force for the
formation of catanionic aggregates [53]. The exothermic enthalpy
3.2.3. Stoichiometry determination of TC-SLS/SDBS ion-pair changes in catanionic mixtures due to electrostatic interaction are
complex (Job’s plot) very well identified in literature [54–56]. The another important
Another important element in the drug-surfactant interaction interaction that hold the oppositely charged molecules close to
is the binding stoichiometry of the reactants. One of the impor- each other is hydrogen bonding which can also play role due to
tant tool for the determination of binding ratio is the method of the presence of butyl amino group as H-donor on TC and carbonyl
continuous variation (Job’s Plot) where the measurements of com- group as H-acceptor on SLS. In region II where the concentration
plex formation is carried out at various combinations of volume of SLS is above the cac, the heat changes turns less exothermic and
fractions of surfactants. To obtain Job’s plot, various volume frac- became similar in magnitude to those measured in the absence
tions of equimolar solution of drug and surfactants were prepared of drug until cmc of SLS reached (14.1 mM). So region II specifies
and mixed. The absorption spectra of both drug and surfactants that after the cac, concentration of monomers is less which makes
were recorded at concentration 0.05 mM of each in the range of interactions somewhat less favourable and favors micelles forma-
200–500 nm where SLS has no absorbance and SDBS absorbance tion [57,58]. Once the SLS micelles formed, again notable change
have been eliminated. TC exhibit one sharp, intense peak at 310 nm in enthalpy have been observed in region III which signifies the
and another small, less intense peak at 226 nm (which later disap- dominance of hydrophobic interactions between SLS micelles and
pear on the addition of surfactant). The Job’s plot method involves hydrophobic part of TC and point towards the incorporation of TC
the measurement of absorbances of various samples and the cor- into hydrophobic core of the micelles. Once the TC solubilized in
rected absorbance (A) of these mixtures are plotted against the the hydrophobic core, no further heat changes have been observed
volume fraction of surfactant solution. The corrected absorbance with more addition of SLS into cell.
 R. Vashishat et al. / Colloids and Surfaces A: Physicochem. Eng. Aspects 498 (2016) 206–217 213

(a) (b)
200
200 60
30 250
250 50
300 300
350 40
350 20
EM(nm) 400 EM(nm) 400 30
450 10
450 20
500 500 10
550 550
600 0 600 0
200 300 400 200 300 400
EX(nm) EX(nm)

(c) 200
(d)
200
250 300
250
300 100
350 200 300
EM(nm) 400 EM(nm)
350
450
100 400
500
550 0
450
600 0
200 300 400
200 300 400
EX(nm)
EX(nm)

Fig. 3. 3D fluorescence plot of (a) 0.05 mM TC (b) 0.05 mM TC + 3.9 mM SLS (c) 0.05 mM TC + 14.2 mM SLS (d) 0.05 mM TC + 1.7 mM SDBS.

Fig. 4. Job’s plot depicting 1:1 stoichiometry for the TC + SLS and TC + SDBS catanionic complexes.

3.3.2. Enthalpy changes for TC-SDBS results into high exothermicity which ascribed to the formation
The phenomenal exothermic heat changes have been observed of TC-SDBS catanionic complex due to ionic binding as in case of
in enthalpogram of SDBS when titrated into TC (Fig. 5b). The TC-SLS (mentioned above). The further addition of SDBS causes the
enthalpy changes have been divided into three regions. In region I mixed micelles to be formed. In region II with increasing concen-
where concentration of SDBS is very low, injection of SDBS into cell tration of SDBS in cell the exothermic effect decreases and above
214 R. Vashishat et al. / Colloids and Surfaces A: Physicochem. Eng. Aspects 498 (2016) 206–217

a b

Fig. 5. Variation of the observed enthalpy (H) with the surfactant concentration for the titration of (a) SLS into water and 2 mM TC (b) SDBS into water and 2 mM TC.

Fig. 6. Size distribution histograms of various aggregates formed in binary mixtures of (a) TC-SLS and (b) TC-SDBS at various mole fractions of TC.

cmc, the observed exothermic enthalpies decreases. The change of As the vesicles formation is also based upon the energetics of the
observed enthalpies should be related with micellar morphology. process so ITC is an excellent tool which can be used to understand
The change in morphology from micelles to vesicles at ␣TC = 0.4 in the change in morphology of the aggregates.
TC-SDBS catanionic mixture were also supported by visual obser-
vation where bluish appearance comes as shown in Fig. 6 and also
confirmed by TEM images (Figure 8) as well as from Dh value of DLS 3.4. DLS measurements
measurements (discussed in Section 3.4). The further addition of
SDBS into cell transform vesicles into micelles and hence observed DLS measurements were further carried out to illustrate the
exothermic enthalpy decreases. The interaction enthalpies were changes in size of aggregates which formed on mixing TC drug
found to be greater than the enthalpy changes for both the vesicle with surfactants at varied concentrations. The size distribution his-
formation and transition of vesicle to micelles. Such ITC mea- tograms of TC-SLS and TC-SDBS aggregates formed at 5 times cmc
surements supporting the micellar morphological transformation solutions are shown in Fig. 6(a) and (b) respectively. In TC-SLS sys-
in catanionic mixtures have been well exemplified in literature tem the Dh values = 1.2 nm and 1.6 nm corresponds to the micelles
[59,60]. Next in region III where the concentration of SDBS is well formed by pure SLS and TC in aqueous solutions respectively. As
above 3.34 mM the enthalpy change is highly endothermic even shown in figures the observed increase in Dh values of TC-SLS sys-
more than the dilution curve. This rise in endothermicity at higher tem with increasing the mole fraction of TC is an indication of the
concentration of SDBS implies that in region III no more interaction growth of the micelles. At ␣TC = 0.1 the mixed micelles slightly grow
between TC and SDBS occur whereas solubilisation of TC drug in the in size with Dh value = 1.5 nm followed by gradually increase with
hydrophobic core of the micelles is favoured due to dominance of further addition of TC molecules upto 0.6 mole fraction of TC. This
strong hydrophobic interactions [61] increasing trend in Dh values from ␣TC = 0.1 to ␣TC = 0.6 speculate
the insertion of TC molecules into SLS micelles due to strong elec-
trostatic interactions between them allowing both TC and SLS to
 R. Vashishat et al. / Colloids and Surfaces A: Physicochem. Eng. Aspects 498 (2016) 206–217 215

approach each other and bigger micelles formed. At ␣TC = 0.6 the
observe Dh value is 36.1 nm and it is unlikely to form spherical
micelles as the maximum length of both SLS and TC is not more than
2 nm. Hence the observed variation in Dh value suggest that there
is anisotropy growth of the micelles. The 0.5 mole fraction of TC has
been neglected and not considered due to milky appearance with
high turbidity which arise due to charge neutralisation between
two amphiphiles. But with further increase in mole fraction of TC
the turbidity disappears and the size of the mixed micelles reduces
due to release of electrostatic repulsions there as a number of TC
molecules causes steric hindrance and bigger micelles crumbled
into smaller. In TC-SLS mixtures the release of electrostatic repul-
sions in cationic rich region is in concordance with our preceding
discussion based on tensiometry profile and interaction parame-
ters. It is worth mentioning that DLS analysis could be considered
as fingerprint of the system evolution rather than absolute probe
of microstructure evolution.
In case of TC-SDBS mixed system the interesting results were
examined throughout all mole fractions of TC (␣Tc = 0.1 to 0.9). The
aqueous solution of pure SDBS forms small sized micelles with Dh
value = 3.1 nm. At ␣Tc = 0.1 the mixture remains clear but the Dh
value changed from 3.1 nm to 3.9 nm implying the formation of
SDBS enriched mixed micelles which grow gently. As the mole frac- Fig. 7. TEM images of vesicles formed in binary mixture of TC-SDBS at 0.4 mole
tion of TC further increased (␣TC = 0.2 and 0.3) turbidity appears in fractions of TC (inset shows zoomed image).
samples and the expeditious growth of mixed micelles with sudden
large increase in Dh value along with the existence of larger aggre-
so SO3 − headgroup of SDBS take up protons from TC and appear
gates have also been perceived. At 0.4 mole fraction of TC micellar
as oil droplet in TC + SDBS mixture. Y. Jiang et al. have also stud-
aggregates disappear and only larger aggregates were found to exist
ied the aggregation behaviour of cationic drug/anionic surfactant
indicating the potentiality of attractive interactions near equimo-
vesicles formed by TC and sodium bis(2-ethylhexyl)sulfosuccinate
larity in TC and SDBS molecules. These larger aggregates can be
(AOT) and also investigated micelles to vesicles transition along
proposed to be formed either due to vesicle formation or due to
with oil droplets in catanionic rich region [64]. Ismail cowerk-
the bridging of cationic head group of TC between intermicellar
ers have also investigated the interaction between TC and sodium
region. As reported earlier the bridging of micelles by hydropho-
deoxycholate (NaDC) and on the basis of DLS and TEM images they
bic head group makes the intermicellar interactions strong, and
have also justified the morphological changes that takes place [65].
larger aggregates formed [62]. Also the existence of strong elec-
In case of TC-SDBS system, in most cationic rich region (␣TC = 0.9)
trostatic as well as hydrophobic interactions in TC-SDBS mixture
again bluish turbid samples formed with Dh values = 58.3 nm and
are well justified by ITC measurements, so the formation of larger
477.3 nm which again signifies the vesicle formation. These tran-
aggregates is probable. These large aggregates can be ascribed as
sition from micelles to vesicles in anionic rich region is favoured
vesicles not only based upon DLS data alone but also clear from Fig.
by electrostatic, hydrophobic and ␲-␲ stacking interactions in
S4 where appearance of turbidity with bluish appearance support
between TC and SDBS and govern spontaneous vesicle formation in
vesicle formation. The only difference between micellar self assem-
TC-SDBS aqueous mixtures. In cationic rich region protonation of
bled larger aggregates and vesicle is their stability. Kumar et al.
SO3 − head group of SDBS forms its correspondence acid whereas
have [63] reported that in the presence of salt the micellar aggre-
again in most cationic rich region catanionic vesicles arise due to
gates disintegrate without leaving effect on vesicles. So to make it
preferential release of TC molecules from mixed system which low-
more clear we also investigated the size of the TC-SDBS mixtures
ers the average spontaneous curvature of the mixed micelles and
(XTC = 0.2, 0.3. 0.4, 0.6) in the presence of 50 mM sodium chloride
facilitates the transition from micelles to vesicles [66]
and observed no change in Dh values. These results also supports
the formation of vesicles in TC-SDBS catanionic mixture. But still,
one cannot predict the morphology of the aggregates formed based 3.5. Effect of head group on the morphology of aggregates
upon DLS measurements alone so TEM measurements were also
undertaken to illustrate the morphology of the mixed aggregates As SLS and SDBS both contain 12 carbon long aliphatic chain but
which proved the vesicle formation. The reality of vesicle formation possess difference in aggregation behaviour. This difference could
get affirmed from the TEM image shown in Fig. 7. These micelles be attributed solely to the properties of polar head groups, as we
to vesicles transitions in catanionic mixtures have been reported have already discussed the effect of polar head group on the cmc
by many research groups [7,64,65]. Recently Mahajan et al. have values of surfactants. The negatively charged head groups of SLS
reported that vesicle-micelle transitions take place upon changing and SDBS bind with cationic part of TC electrostatically, hydropho-
the mixing ratio of surfactants in SDBS-imidazolium ionic liquid bically and also through hydrogen bond. But the another important
in catanionic mixtures [7]. At equimolar concentration (␣TC = 0.5) interaction is ␲-␲ stacking interactions offered by benzene ring of
the sample become curdy white indicates the precipitation due to SDBS and TC and plays important role in determining higher nega-
neutralization of opposite charges from both TC and SDBS. Above tive value of interaction parameter, more exothermic heat changes
equimolarity (␣TC = 0.6 to 0.8) interesting results were observed in and high binding constant in TC-SDBS mixtures. As a consequence
TC + SDBS mixture. In cationic rich region precipitate does not takes of different head groups the transitions from micelles to vesicles
place but turbidity appears initially followed by disappearance with have been observed in TC-SDBS mixtures but not in TC-SLS mixture
continuous stirring and oil like droplets formed. The reason for the due to the reason that in aqueous solution the carboxylate group
appearance of oil droplets is the protonation of SO3 − headgroup of SLS exhibit water ordering properties whereas sulphate group of
of SDBS. As the concentration of TC molecules is more than SDBS SDBS does not [6,67]
216 R. Vashishat et al. / Colloids and Surfaces A: Physicochem. Eng. Aspects 498 (2016) 206–217

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