WA J I D H . A N S A R I , SAHAR NOORI , A N D L E E B Z . N A Q V I , K A B I R - U D - D I N

D E PA RT M E N T O F C H E M I S T RY, 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

Self-association and Interaction of Zwitterionic Surfactants with the

Amphiphilic Drug: A Physicochemical Aspects

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.

Objective:The purpose of this study is to provide better knowledge about the formation of mixed micelles and mixed monolayers of drug-surfactant systems. The aim is optimization of application of drug-surfactant systems.

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, are more proficient of encapsulating both hydrophilic and hydrophobic drugs.

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.

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.

N

CHHC

CH

CH

CH

HC

HC

HC

HCCH

H 2C

CH 2N

CH 3

H 3 C

.HCL

Imipramine hydrochloride

12(-)-2-12(+)

PO

O _

N +

C12H25

CH3

CH3O

O

C12H25

A m phi ph i l i c Dr u g

Z w i t t er i on i c Gem i n i

Gemini and drug mixed micelles

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.

0.025 0.050 0.075 0.1000.0000

0.0005

0.0010

0.0015

0.0020

0.0025

0.0030

cm

c,

cm

cid (

mol)

mole f r act ion of gemini sur f act ant 12(-)-2-12(+)

cmcid

cmc

Fig. 2.Variation of cmc and cmcid with the mole fraction of

12(-)-2-12(+).

-6 -5 -4 -3 -2 -1

30

35

4 0

4 5

50

55

60S

ur

fa

ce

Te

ns

ion

mN

m-1

log C

12(-)-2-12(+) IMP

Fig. 1 . Surface tension plot of pure 12(-)-2-12(+) and

IMP.

The surface excess concentration under the condition of surface saturation (Γmax) can be used as a measure of surface adsorption.

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.

Clog/ nRT303.2

1 max

Amphiphilecmc

(mM)

Γmax.107

(mol m-

1)

Amin

(Å2)βm

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 0.1262

IMP 45.20 14.19 116.93

m1f

m2f

Table. Parameters derived from surface tension measurements for pure gemini surfactant, AMT and mixed systems.

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 to the activity coefficients ( , ) of the two components. The fundamental equations are

and

In all the cases, > , 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)]X(1)/cmcα(1ln[cmc)X(1

]X/cmcαln[cmc)(Xm121

2m1

m111

2m1

2m

1

m111m

)X(1

)X/cmcln(cmcαβ

id1X m

1X

m1f

m2f

0.025 0.050 0.075 0.100

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Xm,

Xid

ea

l

mole f r act ion of gemini sur f act ant 12(-)-2-12(+)

Xm

Xideal

Fig. 3.Variation of Xmand Xid with the mole fraction of 12(-)-2-12(+).

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 are greater than that of .This means that the hydrophobicity of the molecules leads them towards the air/ solution interface and after surface adsorption, micellization takes place.

0adΔG

0.025 0.050 0.075 0.100-80

-70

-60

-50

-4 0

-30

25

30

35

4 0

4 5

G0

m, G

0

ad,

Gm

in

mole f r act ion of gemini sur f act ant 12(-)-2-12(+)

G0

m

G0

ad

Gmin

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.

Fig. 4.Variation of , and Gmin with the mole fraction of 12(-)-2-12(+).

0micΔG 0

adΔG

0micΔG

Stability of Mixed MicellesUV 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.

180 200 220 240 260 280 300 320 340 360

0

1

2

3

4

Absorba

nce

Wavelengt h (nm)

1st 3rd 7th 15th 30th

180 200 220 240 260 280 300 320 340

0

1

2

3

4

Absorba

nce

Wavelent h (nm)

1st 3rd 7th 15th 30th

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.

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.