Journal of Molecular Liquids 167 (2012) 115118

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Journal of Molecular Liquids

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Short Communication

Interaction of amphiphilic drug amitriptyline hydrochloride with -cyclodextrin as studied by conductometry, surface tensiometry and viscometry
Mohd. Sajid Ali a,, Malik Abdul Rub b, Farah Khan b, Hamad A. Al-Lohedan a, Kabir-ud-Din b
a b

Department of Chemistry, College of Science, King Saud University, Riyadh 11541, Saudi Arabia Department of Chemistry, Aligarh Muslim University, Aligarh-202002, India

a r t i c l e

i n f o

a b s t r a c t
Cyclodextrins are very well known to form the inclusion complexes with various drugs owing to their internal cavity. In this paper we have studied the interaction of -cyclodextrin (-CD) with amphiphilic drug amitriptyline hydrochloride (AMT) exploiting conductometry, surface tensiometry and viscometry. It was found that addition of -CD to the drug solution causes the shifting of micellization of amphiphilic drug toward higher concentrations. This conrms the complex formation between the drug and the host molecule as a result of the interaction between them. Surface tension isotherms suggest that the addition of -CD results in the surface tension of the solution to decrease as compared to the pure solution of drug due to the encapsulation of surface active drug inside the hydrophobic cavity of -CD. Similarly, viscosity of the solution decreases drastically on the addition of -CD which further increased on increasing the drug concentration. Free energy of micellization (Gmic) was computed with the help of degrees of micelle ionization obtained from the specic conductivity [AMT] plots. 2012 Elsevier B.V. All rights reserved.

Article history: Received 14 November 2011 Received in revised form 13 December 2011 Accepted 2 January 2012 Available online 14 January 2012 Keywords: Antidepressant drug Amitriptyline hydrochloride Critical micelle concentration -Cyclodextrin

1. Introduction Cyclodextrins are cyclic oligosaccharides which form with the enzymatic degradation of starch and they are consisting of (1,4)-linked D-glucopyranose units. The most common among them are -, - and -cyclodextrins which are composed of six, seven and eight glucose units, respectively. The hydrophobic cavity of the cyclodextrin is capable to encapsulate hydrophobic molecules or the hydrophobic parts present in the molecules [14]. As a result, the solubility of the hydrophobic and amphiphilic compounds increases. Due to this ability, cyclodextrins are of great interests in pharmaceutical chemistry [58]. Their interactions with simple drugs and the formation of inclusion complexes with them have been studied extensively [9]. Cyclodextrins also form complexes with the amphiphilic compounds such as surfactants [1015]. In most of the studies carried out with surfactants, cyclodextrins were found to increase the critical micelle concentration (cmc) of the surfactants as a result of the inclusion complex formation. Several drug molecules (such as, tricyclic antidepressants, phenothiazine tranquilizers) known to possess the amphiphilic behavior, form micelle like aggregates at or above certain critical concentrations [1618]. Their micelles are rather rigid and have low aggregation number as compared to the micelles of the simple surfactants. Amitriptyline hydrochloride, AMT, (Scheme 1) is a tricyclic antidepressant

drug and displays amphiphilic behavior. The drugs belonging to the tricyclic antidepressant category have several overdose disadvantages such as anti-arrhythmic, anti-cholinergic and cardiovascular side effects [19,20]. These effects can be minimized if the drug is suitably vectored to the body with the help of suitable carrier excipient. As is well known, cyclodextrins are one of the best articial receptor for the vectorization of the drugs; they are extensively used in the drug delivery formulation as excipients. In this paper we have studied the interaction of -cyclodextrin (CD) with amitriptyline hydrochloride by using various basic techniques, like, conductometry, surface tensiometry and viscometry as these are some of the primary techniques to study the amphiphilic systems. 2. Materials and methods 2.1. Materials AMT (99%, Sigma, USA) and -CD (99%, Sigma, USA) were used as received. Demineralized double-distilled water of specic conductivity (1 2) 10 6 S cm 1 was used to prepare the stock solutions of the drug and -CD. 2.2. Methods 2.2.1. Conductivity measurements The conductivity measurements were performed on an ELICO (type CM 82T) bridge equipped with platinized electrodes (cell constant = 1.02 cm 1). The conductivity runs were carried out by adding

Corresponding author. Tel.: + 966 598878428; fax: + 966 14679972. E-mail address: smsajidali@gmail.com (M.S. Ali). 0167-7322/$ see front matter 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.molliq.2012.01.004

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4.0 3.5 3.0

10-2 (Scm-1)

2.5 2.0 1.5 1.0 0.5 0.0 0 10 20 30 40 50 60 70 80 90

% -CD (w/v) 0.1 0.2 0.5 1.0

Scheme 1. Structure of amitriptyline hydrochloride.

gradually concentrated AMT stock solution into the thermostated solvent or solvent including -CD at temperature 25 C. The critical micellar concentration (cmc) of the pure AMT used was obtained from the plots of specic conductivity () as a function of the drug concentration. The cmc values were taken from the intersection of the two straight lines drawn before and after the intersection point in the plots (Fig. 1). In case of the -CD-AMT mixtures the cmc was regarded as the apparent critical micelle concentration (cmc*). 2.2.2. Surface tension measurements The equilibrium surface tension was measured using the du Noy ring technique carried out with a Krss K100 tensiometer. In case of pure AMT, the equilibration time was 15 min, whereas the AMT-CD solutions were equilibrated at least for 30 min. Thus, the values of surface tension () were noted when it did not vary with time. The average values of equilibrium were obtained by repeating the measurement three times. The cmc and cmc* values were estimated by the intersection between the two linear portions of log [drug] isotherms. The interfacial adsorption efcacy of the amphiphile measured by the slope of the tensiometric prole near the cmc, is quantied by the Gibbs surface excess (max) [21,22].    1 2 molm 2:303nRT logC

[AMT] (mM)
Fig. 2. Plots of specic conductivity () versus AMT concentration at different concentrations of -CD. The scale shown is for plot denoted as (). Other plots have been shifted upwards by 0.5, 1.0, and 1.5 scale units (1 10 2 S cm 1), respectively.

2.2.3. Viscosity measurements The viscosities were measured using an Ubbelhode suspended level capillary viscometer. The viscometer was always suspended vertically in a thermostat with a temperature stability of 0.1 K in the investigated region. The requisite amount of drug was added in CD solution. These solutions were used as stock solutions to see the effect of drug concentration. A high concentration solution was prepared for drug, and further lower concentrations were made by dilution from above stock. Viscosities of such solutions under Newtonian ow conditions were obtained as described elsewhere [23]. Density corrections were not made since these were found negligible [24]. 3. Results and discussion Fig. 1 shows a specic conductivity prole as a function of concentration of AMT. The intersection point of the two straight lines represents the usual critical micellar concentration (cmc) of AMT and was found to be 0.0334 mol dm 3, which is in accordance to the values reported earlier [16]. The specic conductivity proles of AMT in presence of -CD are given in Fig. 2. We have used various
44

max

and the minimum area of exclusion per molecule at the saturated air/ solution interface (Amin) A min 1020  2  A NA max 2

where R, T, and NA are gas constant, temperature (in Kelvin), Avogadro's number, respectively, C is the total amphiphile concentration in solution and n = 1
3.0 2.5 2.0

42

40

cmc*(mM)

102 (Scm-1)

38

1.5 1.0 0.5 0.0 0 10 20 30 40 50 60

36

34

32 0.0 0.2 0.4 0.6 0.8 1.0

[AMT] (mM)
Fig. 1. Plot of specic conductivity () versus [AMT] at 25 C. Fig. 3. Apparent critical micelle concentration (cmc*) of the drug as a function of -CD concentration.

M.S. Ali et al. / Journal of Molecular Liquids 167 (2012) 115118

117

63 6

54

(Scm-2mol-1)

(N m-2)
45
% -CD (w/v) 0 0.1 1.0

[CD] 0 0.5% 1%

36

10

[AMT] (mM)
Fig. 5. Variation of surface tension with the logarithm of AMT concentration in absence and presence of -CD.

3 0 20 40 60 80

[AMT] (mM)
Fig. 4. Plots of molar conductivity () versus AMT concentration with and without CD. Table 2 Values of cmc, max, and Amin of AMT/water and AMT/-CD/water mixtures obtained from surface tension method. cmc (mN m 1) 106max(mol m 2) 2.38 2.42 3.00 Amin (2) 69.6 68.5 55.3

concentrations of -CD to get a complete insight on the interaction. The drug is supposed to form the inclusion complex with the -CD due to the nonpolar interactions between the hydrophobic cavity and the amphiphilic drug rather to form the micelle and/or to form monolayer at the surface as revealed by the surface tension measurements (vide infra). After the drug monomers will be occupied by the -CD, remaining adsorption of the monomers on the surface begins. When the surface is saturated by the drug monomers the point is called as the cmc* at which formation of the micelles or micelle like aggregates begins [25]. From the above discussion it is obvious that cmc* should be higher than the cmc of the drug. The increase in cmc* (Fig. 3) on increasing -CD is understandable as more amount of drug will be needed to saturate the -CD, hence, a delayed micellization [26]. The cmc of drug increases linearly with -CD concentration (Fig. 3).The intercept of the plot is consistent with the experimental cmc of pure drug. This fact is due to the formation of the inclusion complex PMZ-CD. Since the association between these host and guest species is tighter than that between the monomers to form the micelles [27,28], the addition of drug to the cyclodextrin solution results in the inclusion of the hydrophobic moiety of the drug into the cyclodextrin cavity. The formation of micelles starts when the cyclodextrin becomes complexed with the drug monomers. The molar conductivity () was calculated using 0 1000C where and 0 are specic conductance of the solutions and water, respectively, and C is the drug concentration in mol dm 3. The molar conductivities for the pure drug and drug-CD aqueous
Table 1 Critical micelle concentration, degree of micelle ionization (), free energy of micellization (Gmic) associated with the solution properties of -CD and AMT at 25 C evaluated on the basis of conductometric measurements. % -CD (w/v) 0.0 0.1 0.2 0.5 1.0 1 0.57 0.61 0.61 0.58 0.55 cmc (mol dm 3) 0.0334 0.0346 0.0356 0.0389 0.0430 Gmic (kJ mol 1) 12.23 11.78 11.64 11.63 11.52

AMT AMT + 0.1% -CD AMT + 1.0% -CD

36.3 36.0 36.0

systems are given in Fig. 4. In general, the molar conductivity decreases as -CD is added, the reason being that as the drug ions become complexed by -CD, they become less effective as charge carrier due to the decreased diffusion coefcient of the complex, as compared to the drug alone [29]. The degree of micelle ionization () was calculated by taking the ratio between the slopes of the linear portions above and below the break point in the conductivity proles. The larger value of for the complex micelles is indication of an increased degree of ionic dissociation (Table 1) as a result of the interaction of amphiphile with macromolecule. The free energy of micellization, Gmic, can be calculated using the following equation [30] Gmic RT 2 lncmc: 3

1.6

% -CD (w/v) 0 1.0 2.0

1.4

1.2

1.0

0.8 0 20 40 60 80 100

[AMT] (mM)
Fig. 6. Relative viscosity as a function of AMT concentration in presence and absence of -CD.

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On increasing the concentration of -CD, Gmic becomes slightly less negative which indicates that the presence of -CD makes the process less feasible and can be explained on the basis that more CD will be able to encapsulate more drug monomers and the amount of drug needed to form the micelle will obviously increase. Fig. 5 describes the effect of low and relatively high concentration of -CD on the surface tension isotherm of AMT. -CD does not show any surface activity in the present system. It is remarkable that addition of -CD causes an increase in the surface tension that means the complex is not surface active rather the drug is being pulled by the hydrophobic cavity of the oligosaccharide and eliminated from the surface [11,31]. As a result the surface tension of the ternary mixture (AMT/-CD/water) increases as compared to the binary mixture of AMT/water. The increase in surface tension becomes more prominent as we increase the concentration of -CD, of course, due to the more exclusion of the drug from the surface for assembling the inclusion complex. In the presence of -CD more amount of drug is needed to attain the constant value of surface tension, i.e., the apparent critical micelle concentration, cmc*. The value of surface tension reaches to almost constant value for all the mixtures (AMT/water as well as AMT/-CD/ water) as the concentration of AMT reaches to the respective cmc* values. The values of cmc* obtained from surface tension measurements are in accordance with observed conductometrically. Various surface parameters obtained from the surface tension measurements are enlisted in Table 2. It is noticeable from Fig. 6 that relative viscosity of the binary mixture of AMT/water and ternary mixture of AMT/-CD/water rst decreases on adding small amount of the drug followed by the gradual increase on further increasing the drug concentration. In case of the ternary systems there is a steep rise in the relative viscosity after the concentration reaches near to their respective cmc*. The initial decrease in r in premicellar region is mainly due to the lowering in water structure by the hydrophobic portions of the AMT [32]. The r remains almost unchanged as the concentration approaches the cmc and starts increasing on with further increase in concentration owing to the formation of micelles [33]. In case of ternary systems the steep rise near cmc* may probably be due to the possible cluster formation of the micelles of the drug around the cyclodextrin molecule due to the interaction of cationic head groups of drug and polar hydrophilic surface of the host molecule [34]. 4. Conclusions The interaction between cationic amphiphilic drug amitriptyline hydrochloride (AMT) with -cyclodextrin (-CD) was studied. It was found that apparent critical micelle concentration (cmc*) increases on increasing the -CD concentration. Gmic becomes less negative on increasing the -CD concentration. The micellization

shifted to the higher concentrations due to the involvement of monomers in inclusion complex formation. Surface tension measurements expose that the -CD was capable to eliminate the amphiphilic drug from the surface. Acknowledgment The authors extend their appreciation to the Deanship of Scientic Research at King Saud University, Riyadh, Saudi Arabia, for funding the work through the research group project no. RGP-VPP-148. References
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