1. Self-association and Interaction
of Zwitterionic Surfactants with
the Amphiphilic Drug:
A Physicochemical Aspects
WA J I D H . A N S A R I ,
SAHAR NOORI,
ANDLEEB Z. NAQVI, KABIR-UD-DIN
D E PA R T M E N T O F C H E M I S T R Y, A L I G A R H M U S L I M
U N I V E R S I T Y, A L I G A R H , 2 0 2 0 0 2 I N D I A

2. Objective:
The purpose of this study is to provide better knowledge about the
formation of mixed micelles and mixed monolayers of drugsurfactant systems. The aim is optimization of application of
drug-surfactant systems.
The most vital issues of a pharmaceutical formulation are to successful delivery of
the therapeutic agent to the target organ at significant levels, with reducing their side
effects and discomfort to the patient. In which aqueous solubility of solid drugs is a
major problem.
 Drug solubility affects the pharmacokinetics such as transport, release and
absorption. Drugs with low aqueous solubility often show inadequate or variable
bioavailability which hampers their applicability.
Two main aspects of successful drug formulation are its solubility and stability. The
solubilizing system must be able to solubilize the required concentration of the drug.
Also, the system must be such that the drug remains stable in it.
Some of the methods used to modify drug solubility are micronization, oil
formulation, complexation, use of prodrugs, cosolvency, chemical modification, pH
adjustment, hydrotropy and solubilization in micelles / microemulsions.

3. Now day’s surfactant micelles acquired rising scientific interest as an alternative
prospective drug delivery vehicle.
 The self-association of surfactants is governed by hydrophobic interactions between
the nonpolar alkyl chains and the electrostatic interactions of the polar or ionic head
groups.
 A clear understanding of the self-aggregation mechanism of amphiphilic drugs and
their interactions with surfactants in aqueous solution is of large importance in the
reasonable formulation of more efficient drug delivery systems .
The surfactant micelles have numerous importances, such as more micellar
stability, lesser care in handling and storage and lower in price.
Furthermore surfactant micelles, like liposomes,
encapsulating both hydrophilic and hydrophobic drugs.
are more proficient of
The encapsulation of drugs in micelles can minimize drug degradation and
inactivation after administration, prevent undesirable side effects, and increase drug
bioavailability and targeting to the pathological area.

4. Surfactants can be used in pharmaceutics as drug carriers. Keeping this in
mind we have studied micellization behaviour in aqueous solutions and
adsorption behavior at air/water interface for heterogemini zwitterionic
surfactant 12(-)-2-12(+) and antidepressant drug imipramine hydrochloride
(IMP) mixed systems.
This drug suffers from anticholinergic, cardiovascular and antiarrhythemic
side effects. These side effects can be reduced by using IMP with a carrier.
HC
HC
H
C HC
Amphiphilic
Drug
H
CH C
CH
C
H
N
C
H
Zwitterionic
Gemini
CH
O
_
O
H2C
H3C
.HCL
P
CH2
O
N+
CH3
O
N
C12H25
CH3
Imipramine
hydrochloride
CH3
Gemini and drug
mixed micelles
C12H25
12(-)-2-12(+)

5. Result and discussion:
The surface tension arises due to the presence of cohesive forces among the
molecules. The interface behaves as a stretched membrane and has a
particular value of surface tension.
When an amphiphile is dissolved in water, to avoid interaction of its
hydrophobic tails with water, the amphiphile molecule prefers to remain at
the air/water interface with its head groups lying at the interface. This
reduces the tension at the surface and surface tension value decreases.
After the saturation of interface, the excess amphiphile molecules tend to
self-associate in the bulk solution to form micelles and surface tension
becomes constant. This concentration is taken as critical micelle
concentration (cmc).
In the IMP and zwitterionic gemini 12(-)-2-12(+) system cmc values
decrease sharply as the surfactants are added, i.e., at α1= 0.025 cmc values
decrease from 45 mM to 2 or less than 2 mM. However, amphiphiles with
different structures usually mix nonideally.

6. 0.0030
12(-)-2-12(+)
IMP
55
cmc, cmcid (mol)
Surface Tension mNm
cmcid
cmc
0.0025
-1
60
50
45
40
0.0020
0.0015
0.0010
0.0005
35
0.0000
30
0.025
-6
-5
-4
-3
log C
-2
0.050
0.075
0.100
-1
Fig. 1 . Surface tension plot of
pure 12(-)-2-12(+) and IMP.
mole fraction of gemini surfactant 12(-)-2-12(+)
Fig. 2.Variation of cmc and cmcid
with the mole fraction of
12(-)-2-12(+).

7. The surface excess concentration under the condition of surface saturation (Γmax) can
be used as a measure of surface adsorption.
max
1
2.303nRT
/ log C
Although the Γmax values for mixture are always smaller than that of pure
components.
Γmax increase with increase in gemini surfactants content in the mixture. May be the
negative charge on gemini is interacting attractively with the positive one on the drug
resulting in compact surface and Γmax increases.
The minimum area per molecule (Amin) in Å can be calculated by (NA Γmax)-1.1020
The trend is opposite of Γmax, i.e., with increase in α1, Amin decreases. The values of
mixture are always greater than single components
The drug-surfactant solutions have greater preference to be adsorbed at air/ water
interface as compared to pure drug.

8. Table. Parameters derived from surface tension measurements
for pure gemini surfactant, AMT and mixed systems.
cmc
(mM)
Γmax.107
(mol m-1)
Amin
12(-)-2-12(+)
0.073
21.50
77.20
0.1
0.345
13.98
118.71
-6.774
0.6325
0.0244
0.075
0.356
12.11
137.08
-7.582
0.5146
0.0233
0.05
0.916
11.88
139.75
-4.222
0.8044 0.0802
0.025
1.648
8.30
199.80
-3.840
0.7620
IMP
45.20
14.19
116.93
Amphiphile
βm
(Å2)
fm
1
fm
2
0.1262

9. The results of cmc and cmcid indicate attractive interactions between the components. and
extent of interactions are characterized by an interaction parameter (βm) which is also related
m
m
to the activity coefficients ( f1 , f 2 ) of the two components. The fundamental equations are
m
m
(X1 )2 ln[cmc α1 /cmc1 X1 ]
m
and βm ln(cmcα1/cmc1X1 )
1
m
m
m
(1 X1 )2
(1 X1 )2 ln[cmc (1 α1 )/cmc2 (1 X1 )]
id
m
In all the cases, X1 > X 1 , i.e., the mixed micelles are poorer in surfactants over their
values in ideal mixtures. As the gemini surfactants are more hydrophobic than the drug,
ideally the micelles should contain surfactant upto 90-95%. However, mixed micelles contain
some drug molecules also, may be because of the negative charge on one of the head groups
of zwitterionic surfactants.
1.00
m
X
ideal
X
0.95
ideal
0.80
X , X
Fig. 3.Variation of Xmand
Xid with the mole fraction of
12(-)-2-12(+).
0.85
m
0.90
0.75
0.70
0.025
0.050
0.075
0.100

10. Thermodynamics of mixing:
The standard Gibbs energy of micellization the values are all negative confirming that the
process of micellization is spontaneous .Presence of a gemini surfactant makes the process of
micellization more spontaneous than for pure drug.
The negative values of standard Gibbs energy of adsorption indicating the process of
adsorption to be spontaneous. Moreover, the absolute values of ΔG 0 are greater than that of
ad
ΔG 0 .
mic
This means that the hydrophobicity of the molecules leads them towards the air/ solution
interface and after surface adsorption, micellization takes place.
Gmin is the minimum free energy of
the given surface with fully adsorbed
amphiphile molecules. The smaller is
the value of Gmin, the more stable
surface forms.
45
ad
35
G
25
G ad
Gmin
,
m
0
G
0
, ΔGad
Fig. 4.Variation of ΔG
and Gmin with the mole fraction of
12(-)-2-12(+).
0
mic
0
30
G
0
, Gmin
40
m
0
-30
-40
-50
-60
-70
-80
0.025
0.050
0.075
0.100
mole fraction of gemini surfactant 12(-)-2-12(+)

11. Stability of Mixed Micelles
UV spectra of pure drug as well as its mixture with zwitterionic surfactant
just after preparation and after 3, 7, 15 and 30 days. The spectra shows
absorption maxima at around 210 to 260 nm. There is hardly any change in
spectra even after 30 days implying that the mixed micelles are quite stable for
the period.
Absorbance
3
2
1
1st
3rd
7th
15th
30th
4
3
Absorbance
1st
3rd
7th
15th
30th
4
2
1
0
0
180
200 220 240 260 280 300 320 340 360
Wavelength (nm)
180
200
220
240
260
280
300
320
Wavelenth (nm)
Fig. 4. UV-vis spectra of 0.075 mole fraction ( 1) of gemini
surfactant and pure IMP at just after preparation, 3, 7 15 and 30
days.
340

12. Conclusion:
The cmc values and interaction parameter (βm) suggest strong
attractive interactions in mixed micelles.
Synergism in the properties of binary mixtures that may be
exploited in their application in industrial preparations and
pharmaceutical formulations because the non-ideality of mixing
in binary mixtures of amphiphilic compounds.
The micelles of drug-gemini surfactant are stable for at least
30 days at room tempreature. Therefore, this formulation
should be ideally stored.
Surfactant micelles provided by the large drug solubility
potential without concurrent increase in vehicle affinity for the
drug.