J. Chem. Thermodynamics 69 (2014) 12–18

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J. Chem. Thermodynamics

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Interaction of cephradine monohydrate withCetyldimethylethylammonium Bromide

0021-9614/$ - see front matter � 2013 Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.jct.2013.09.030

⇑ Corresponding author. Fax: +880 2 7791052.E-mail address: ahoque_ju@yahoo.com (M.A. Hoque).

Mohammed Delwar Hossain, Md. Anamul Hoque ⇑Department of Chemistry, Jahangirnagar University, Savar, Dhaka 1342, Bangladesh

a r t i c l e i n f o

Article history:Received 11 April 2013Received in revised form 19 September 2013Accepted 20 September 2013Available online 2 October 2013

Keywords:Cephradine monohydrateCetyldimethylethylammonium BromideCritical micelle concentrationEnthalpy changeMolar heat capacity

a b s t r a c t

Interaction of cephradine monohydrate (CDM) with Cetyldimethylethylammonium Bromide (CDMEAB)has been studied by conductance measurements in pure form and in the presence of salts like potassiumchloride (KCl) and potassium sulphate (K2SO4) over the temperature range of (298.15 to 318.15) K. Fromconductivity vs. surfactant concentration plots, two critical micelle concentrations like c�1 and c�1 wereobtained for (CDM + CDMEAB) systems. The variation of c⁄ values of CDMEAB in the presence of CDMis the indication of the interaction between CDM and CDMEAB. For the (CDM + CDMEAB) system, thevalues of c⁄ values are higher in magnitude in contrast to that of pure CDMEAB in water over the rangein temperature studied. In aqueous solutions of KCl and K2SO4, the c⁄ values are changed with theincrease of the concentration of salts and hence the micellization is dependent on salt concentration.The DG0

m values were negative and the spontaneity of micellization process is found to be increased withincrease of temperature. The values of DH0

1;m and DS01;m indicated that the drug mediated CDMEAB aggre-

gation in water was controlled at lower temperatures while at higher temperatures the aggregation wasboth enthalpy and entropy controlled. The DH0

2;m and DS02;m values revealed that the micellization in water

was both enthalpy and entropy controlled at lower and higher temperatures though the effect of entropyat middle temperature was dominant. The results indicated that binding interactions between CDM andCDMEAB are both electrostatic and hydrophobic in nature while the contribution of hydrophobic inter-action is dominant at lower temperatures. In aqueous solution of KCl, The DH0

m and DS0m values indicated

that the micellization was both enthalpy and entropy controlled at lower temperature while the processwas entirely entropy driven at higher temperatures. In case of aqueous K2SO4 solution, the micellizationwas mostly entropy driven over the range of temperatures studied.

The negative molar heat capacity change (DmC0p) for micelle formation shows that DH0

m comes to bemore negative as the temperature rises. The small DmC0

p and the overall positive binding entropy indicateslight structural rearrangement of CDMEAB micelle in the course of binding with CDM. The presence oflinear correlation between DH0

m and DS0m values was perceived in all cases.

� 2013 Elsevier Ltd. All rights reserved.

1. Introduction

Surfactants are used extensively in pharmaceutical formula-tions to facilitate the preparation, patient tolerability, effectivedosage form and also be used as diluents, disintegrating agents,suspending agents, solubilizing agents and emulsifying agents[1–4]. Thus surfactants become imperative constituent in both bio-logical and applied systems. Surfactant micelles have been exten-sively utilized as an approach to enhance the water solubility ofmany pharmaceutical ingredients that stands for an arduousproblem in formulation of an acceptable dosage form [5–9]. Thephysico-chemical interaction of drugs with surfactant micellescan be imagined as an approximation for their interactions with

biological surfaces. This provides an understanding into more com-plex biological processes, such as the passage of more complicatedbiological and prototype drugs through the cell membranes as wellas encapsulates to counteract the side effect of drugs. Surfactantshave versatile applications as physical models anticipated to sim-plified model of biomembranes [10]. For this, the feedback of inter-actions between surfactants and drugs has been a topic of centraland pragmatic research in the preceding decades [2,11].

Cephradine monohydrate (scheme I) is an orally administratedbroad-spectrum first-generation antibiotic which is used in theremedial of bacterial infections to wit streptococcal tonsillitis, skininfections, urinary tract and reproductive tract. The various physi-cochemical interactions in the body are always taking place in bio-logical fluids where potassium salts of different forms are presentand may influence the interactions of biological systems. Althougha number of studies on the interaction of surfactants with drug

N

SNH

COOH

O

NH2H

O CH3. H2O

SCHEME I. Cephradine monohydrate (CDM).

CH3CH2

H2C

CH2

H2C

CH2

H2C

CH2

H2C

CH2

H2C

CH2

H2C

CH2

H2C

CH2

+NCH2

H3C CH3-Br

CH3

SCHEME II. Cetyldimethylethylammonium Bromide (CDMEAB).

M.D. Hossain, M.A. Hoque / J. Chem. Thermodynamics 69 (2014) 12–18 13

molecules are reported in the literature [4,12,13], to the best of ourknowledge very little is known about the interaction of cephalo-sporin drugs with ionic surfactants. In our earlier paper, interactionof cephalosporin drugs with ionic surfactants in pure water and inpresence of salt was reported [12,14,15]. In continuation of thestudy, the interaction of cephalosporin drug such as CDM with amodel cationic surfactant CDMEAB (scheme II) in pure water aswell as in the presence of salts like KCl and K2SO4 was carriedout using conductometric technique. To illustrate the CDM–CDMEAB interactions, the values of critical micelle concentration(c⁄), fraction of counter ion binding (b) and thermodynamic param-eters such as DG0

m, DH0m, DS0

m and DmC0p associated with the CDM

mediated CDMEAB micellization in pure water as well as in KCland K2SO4 solutions have been evaluated.

2. Materials and method

CDMEAB (Acros Organics, USA), CDM (USP standard sample),KCl (BDH, England) and K2SO4 (Merck, Mumbai) were used in thisstudy without any further treatment and their purity in mass frac-tion unit were 0, 99, 0.98, 0.995 and 0.99 respectively. Distilled–deionized water of specific conductance 1.5–2.0 lS � cm�1 wasused in all preparations. A summary of the provenance and purityof the studied materials is given in table 1a.

The specific conductances of the (CDM + CDMEAB) systemsboth in water and in aqueous salts solution were measured usinga 4510 conductivity meter (Jenway, UK) with a temperature-com-pensated cell (cell constant provided by manufacture is 0.97 cm�1)using the procedure reported in the literatures [12,14–18]. Theaccuracy of the measured conductances was within ±0.5%. The con-centrated CDMEAB (50 mM) solution was progressively added tothe CDM solution (0.5258 mM) taken in a test tube and then theconductances were measured after thorough mixing as well asallowing time for temperature equilibration. The concentration ofCDM was kept constant as 0.5258 mM to study the effect of tem-perature both in water and aqueous solution of salts studiedwhereas the concentration of CDM was varied in the case of study-ing the effect of the concentration of drug on the micellization ofpure CDMEAB. The desired constant temperature was maintainedusing RM6 Lauda circulating water thermostated bath with preci-sion of ±0.1 K. To examine the effect of salts such as KCl andK2SO4 on the interaction of CDM with CDMEAB, both the CDMand CDMEAB solutions were prepared in such a way that bothsolutions contain the identical concentration of salt.

3. Results and discussion

The specific conductance of drug solution is found to be chan-ged with the addition of CDMEAB surfactant in pure water and inthe presence of salts. The values of (CDM + CDMEAB) system inwater at temperature 303.15 K for the gradual addition of CDMEABto CDM solution are presented in table 1b. Figure 1 is a distinctiveplot of specific conductivity (j) vs. concentration of CDMEAB forpure CDMEAB and (CDM + CDMEAB) system in water and/or inaqueous solution of salt at 303.15 K. The sudden changes in con-ductivity (j) at certain concentration of surfactant produces sharp

break point in the plots and the concentration corresponding to thebreak points are taken as the critical micelle concentration[12,14–20]. Two such break points are observed for both pureCDMEAB and (CDM + CDMEAB) systems both in pure water andin aqueous solutions of salts. These critical micelle concentrationsare labeled as c�1 and c�2 in this study. Such more than one c⁄ value isalso reported in the literature by others and us [14–20]. For pureCDMEAB, c�1 value indicates the formation of free micelle and thec�2 value refer to the structural micellar change in solution fromone shape to other [21]. For the (CDM + CDMEAB) systems, the c�1value is also the critical micelle concentration of CDMEAB whichdepends on the drug concentration. The c�2 values can also indicatethe transition of the formed CDMEAB micelle to a other shape. Thedegree of ionization of micelles (a) was determined from the quo-tient of the slopes of the two intersecting straight lines correspond-ing to the upstairs and beneath c⁄ [14–16,22–24]. By deducting thevalue of a from unity, the fraction of counter ion binding, b at c⁄

was determined.The values of c⁄ and b in water containing different concentra-

tions of drugs at 303.15 K are presented in table 2. The values ofc⁄ for pure CDMEAB in water is found to be changed with theaddition of CDM and the c⁄ values for (CDM + CDMEAB) systemare higher in magnitude compared to those of pure CDMEAB inwater [14]. Also there is an alteration in the c⁄ values for(CDM + CDMEAB) system with the variation of the concentrationof drug at 303.15 K which point out the interaction between drugand surfactant. The values of c⁄ and b for (CDM + CDMEAB) systemat 303.15 K temperature in the presence KCl and K2SO4 is docu-mented in table 3. The c�1 values of (CDM + CDMEAB) system insalts solution are found to be lower in magnitude compared tothe c�1 values in water whereas the c�2 values in salts solution arehigher compared to those in water for pure surfactant. Also thec�1 values are found to decrease with increase of the concentrationof KCl whereas for K2SO4, the c�1 values decrease firstly, then tendto increase with increase of the concentration of K2SO4. Thisreveals the increase of interaction between CDM and CDMEABand the aggregation of CDM and CDMEAB starts at lower concen-tration in salts solution compared to that in water. A considerabledecrease of c�1 values reveal that drug–surfactant interaction ismuch favored in aqueous salts solution where the effect is muchpronounced in K2SO4 solution compared to that in pure water.The decrease in the c⁄ value in these cases is observed mainlydue to the decrease in depth of the ionic atmosphere surroundingthe ionic head groups in the presence of the additional electrolyteand the resulting decrease of electrical repulsion in the middle ofthem in the micelle [9]. With addition of salt, a decrease of c⁄ val-ues was reported for the micellization of pure ionic surfactants andalso for (drug + surfactant) systems [14,17,25]. In the presence ofK2SO4 for (CDM + CDMEAB) systems, c�2 values are much higherin magnitude compared to those of the c�2 values in both purewater and aqueous KCl solution. Also the c�2 values increase withthe increasing concentration of K2SO4 which reveal that theamount of bound surfactant to drug gradually increases with saltconcentration and thus micellization takes place at higher surfac-tant concentration. The entire consequences of an electrolyte comeinto view to limit on the sum of its effects on the drug and surfac-tant molecule in associate with the aqueous phase. Hydrophilicgroups of the surfactant molecules are in associate with the aque-ous phase in mutually the monomeric and micellar forms of the

TABLE 1aProvenance and purity of the materials studied.

Chemical Source Mass fractionpurity

Specific conductance/ls � cm�1

CDMEAB Acros Organics 0.99CDM Drug

International0.98

KCl BDH 0.995K2SO4 Merck 0.99H2O Distilled

deionised1.5–2.0

TABLE 1bThe values of the specific conductance (j) measured for the (CDM + CDMEAB) systemin water at T = 303.15 K.

cCDM/mM cCDMEAB/mM ja/lS � cm�1

0.5258 0.00 6.110.5244 0.13 13.970.5230 0.27 20.800.5216 0.40 28.400.5203 0.53 35.400.5189 0.66 41.700.5175 0.79 47.400.5162 0.92 51.800.5148 1.04 54.900.5135 1.17 57.300.5121 1.30 59.600.5108 1.42 61.500.5095 1.55 63.300.5082 1.68 65.000.5069 1.80 66.600.5056 1.92 68.000.5030 2.17 71.200.5004 2.41 74.400.4979 2.65 76.700.4954 2.89 79.500.4929 3.13 82.300.4905 3.36 84.900.4881 3.59 87.300.4857 3.82 89.300.4833 4.04 91.400.4809 4.27 93.600.4774 4.60 96.600.4740 4.93 99.600.4706 5.25 102.300.4672 5.57 105.000.4639 5.88 107.400.4607 6.19 109.900.4575 6.50 112.500.4543 6.80 114.700.4512 7.09 117.000.4481 7.39 118.800.4451 7.67 120.900.4421 7.96 122.800.4391 8.24 124.700.4353 8.61 127.100.4315 8.97 129.30

a The error in the measurement of k values is ±0.05.

14 M.D. Hossain, M.A. Hoque / J. Chem. Thermodynamics 69 (2014) 12–18

surfactant while the hydrophobic groups are in associate with theaqueous phase only in the monomeric form. Thus the consequenceof the electrolyte on the hydrophilic groups in the monomeric andmicellar forms may abolish each other, withdrawal the hydropho-bic groups in the monomers as the moiety most likely to beconceited by the toting of electrolyte to the aqueous phase.

The values of c⁄ and b at different temperatures for(CDM + CDMEAB) system in pure water and in the presence of saltsare presented in tables 4 and 5 respectively. The values of c⁄ for(CDM + CDMEAB) system in pure water decrease initially up tocertain temperature, reach a point of minimum and then start toincrease with further with rise of temperature. The c⁄ values for

(CDM + CDMEAB) system in aqueous KCl solution increase initiallyup to certain temperature, reach a point of maximum and thenstart to decrease again with further with rise of temperature. Thec�2 values for (CDM + CDMEAB) system in the presence of K2SO4 de-crease initially up to certain temperature, reach a minimum andthen tend to increase with further increase of temperature. Thechange of c⁄ values with temperature can be explained with thechange of the modes of hydration surrounding the surfactantmonomers as well as the drug mediated CDMEAB micelles. Boththe hydrophobic and hydrophilic hydrations are possible in mono-meric form of surfactant whereas only hydrophilic hydration islikely for micellized CDMEAB. Both types of hydrations are ex-pected to change with change of temperature. A decrease of hydro-philic hydration is known to favor the micelle formation while adecrease of hydrophobic hydration with the increase of tempera-ture disfavours the micelle formation [9,24]. Thus the extent ofthese two factors determine whether the c⁄ values increase or de-crease over a particular temperature range.

The c�1 values in the presence of KCl and K2SO4 are lower in mag-nitude contrast to those in aqueous medium and the outcome ismore pronounced in presence of K2SO4. This reduction of c⁄ valuesmay be due to the decrease in the electrical repulsion among thecharged head groups in the micellar surface in electrolytic solution.This upshot reveal that CDM–CDMEAB micelles are formed morefavorably in aqueous KCl and K2SO4 solutions compared to thatin water. For the identical ionic strength (I) of both KCl andK2SO4, the c�1 values for (CDM + CDMEAB) system are lower in mag-nitude compared to those in the presence of KCl. This may be ow-ing to the point that the chloride (Cl�) ion, a moderate chaotrope,as a large singly charged ion with a low charge density breakswater structures and destabilizes aggregation of surfactant mole-cules exhibiting weaker interactions with water than water withitself and thus interfering little in the hydrogen bonding of the sur-rounding water. The sulfate ion (SO2�

4 ), a strong kosmotrope, as asmall multi charged ion with a high charge density interacts withwater more strongly as a water structure maker and stabilizeshydrophobic aggregates of surfactant molecules parading strongerinteractions with water molecules than water with itself andtherefore capable of breaking water–water hydrogen bonds. Kos-motropes stay behind hydrated adjacent the water surface, whilethe chaotropes drop their hydration sheath. Thus the hydrogenbonding between water molecules is more broken in the proximatevicinity of kosmotropes which salt out the hydrophobic chains ofsurfactants from aqueous medium and thus lowers the c⁄ valuesof the surfactant system compared to that of chaotrope.

The thermodynamic parameters of (CDM + CDMEAB) systemcontaining 1:1 electrolyte type surfactant were determined onthe basis of mass action model using the following equations[12–16,24–28]:

DG0m ¼ ð1þ bÞRT lnðc�Þ; ð1Þ

DH0m ¼ �ð1þ bÞRT2ð@ ln c�=@TÞ; ð2Þ

DS0m ¼ DH0

m � DG0m

� �=T; ð3Þ

where values of c⁄were in used in mole fraction unit. ln(c⁄) vs. T plot(figure 2) were used to compute DH0

m and the plots were found to benonlinear. A tangent was drawn at each temperature of the nonlin-ear plot and the slope of the tangent at each temperature was takenas equal to oln(c⁄)/oT [14,15,24,28,29].

The values of thermodynamic parameters for (CDM + CDMEAB)system in pure water and in the presence of salts like KCl andK2SO4 are presented in table 6. The DG0

1;m and DG02;m values for all

the cases are found to be negative and the negative valuesincreases with rise of temperature which indicates that the

0 2 4 6 8 100

20

40

60

80

100

120

140

κ (μ

S. cm

-1)

cCDMEAB (mM)

cCDMEAB (mM) cCDMEAB (mM)

cCDMEAB (mM)

(a)

0 1 2 3 4 5 6 7 8 9

20

40

60

80

100

120

140 (b)

0 1 2 3 4 5 6 7 8 9

100

120

140

160

180

200

κ (μ

S. cm

-1)

(c)

0 2 4 6 8 10 12 14 16 18

140

160

180

200

220

(d)

κ (μ

S.cm

-1)

κ (μ

S.cm

-1)

FIGURE 1. Plot of specific conductivity (k) vs. concentration of CDMEAB for (a) pure CDMEAB in water, (CDM + CDMEAB) system (b) in water, (c) in aqueous solution of KCl,and (d) in aqueous solution of K2SO4 at T = 303.15 K.

TABLE 2Values of c⁄ and b for the (CDM + CDMEAB) system in water containing differentconcentrations of CDM at 303.15 K.

cdrug/mM c�1/mM c�2a/Mm b1 b2

0.00b 0.90 3.70 0.79 0.860.0421 0.95 5.05 0.81 0.880.5258 0.97 4.05 0.77 0.871.0516 1.00 4.33 0.76 0.861.5774 1.04 4.73 0.78 0.872.1032 1.00 4.98 0.77 0.87

a The error in the c�2 values is in the range of ±0.05–0.1 mM.b Reference [14].

TABLE 3Values of c⁄ and b for (CDM + CDMEAB) system containing 0.5258 mM CDM in thepresence of salts KCl and K2SO4 at 303.15 K temperature.

Salts csalt/mM c�1/mM c�2a/mM b1 b2

KCl 0.10 0.86 6.66 0.77 0.870.50 0.79 4.39 0.79 0.871.00 0.63 3.86 0.80 0.891.50 0.61 6.43 0.85 0.842.00 0.53 7.78 0.88 0.88

K2SO4 0.10 0.57 5.66 0.76 0.860.33 0.49 7.23 0.73 0.840.50 0.52 8.50 0.81 0.881.00 0.55 9.96 0.71 0.80

a The error in the c�2 values is in the range of ±0.05–0.1 mM.

TABLE 4Values of c⁄ and b for the pure CDMEAB and (CDM + CDMEAB) systems in watercontaining 0.5258 mM CDM at different temperatures.

System T/K c�1/mM c�2a/mM b1 b2

CDMEABb 298.15 0.88 4.10 0.79 0.87CDM–CDMEAB 298.15 1.00 4.19 0.77 0.86

303.15 0.97 4.05 0.77 0.87308.15 0.95 3.90 0.77 0.87313.15 1.01 3.75 0.77 0.88318.15 1.11 4.03 0.78 0.88

a The error in the c�2 values is in the range of ±0.05–0.1 mM.b Reference [14].

TABLE 5Values of c⁄ and b for the (CDM + CDMEAB) system containing 0.5258 mM CDM inaqueous solution of salts at different temperatures.

Salts I/mM T/K c�1/mM c�2a/mM b1 b2

KCl 1.00 298.15 0.47 3.80 0.82 0.89303.15 0.68 3.86 0.80 0.89308.15 0.63 3.90 0.83 0.90313.15 0.59 3.85 0.84 0.91318.15 0.55 3.74 0.82 0.90

K2SO4 1.00 298.15 0.43 7.51 0.73 0.83303.15 0.49 7.23 0.73 0.84308.15 0.45 6.64 0.79 0.89313.15 0.41 7.05 0.68 0.82318.15 0.38 7.44 0.71 0.85

a The error in the c�2 values is in the range of ±0.05–0.1 mM.

M.D. Hossain, M.A. Hoque / J. Chem. Thermodynamics 69 (2014) 12–18 15

295 300 305 310 315 320-11.3

-11.2

-11.1

-11.0

-10.9

-10.8

-10.7 ln

(c* 1)

T

(a)

300 305 310 315 320-12.2

-12.0

-11.8

-11.6

-11.4

-11.2

ln(c

* 1)

T (K)

(b)

300 305 310 315 320-12.2

-12.0

-11.8

-11.6

-11.4

-11.2

-11.0

-10.8

ln(x

* c 1)

T (K)

(c)

FIGURE 2. ln(c�1) vs. T plot of (CDM + CDMEAB) system (a) in water, (b) in aqueous solution of KCl, and (c) in aqueous solution of K2SO4.

TABLE 6Values of the thermodynamic parameters for the micellization of the (CDM + CDMEAB) system containing 0.5258 mM CDM in water and in aqueous salts solution at differenttemperatures.

Medium I/mM T/K DG01;m DG0

2;ma DH0

1;m DH02;m

b DS01;m DS0

2;mc DC0

1;m DC02;m

kJ �mol�1 kJ �mol�1 J �mol�1 � K�1 kJ �mol�1 � K�1

H2O 0.00 298.15 �48.07 �43.76 40.81 �3.01 298.10 136.67 �8.40 4.96303.15 �49.21 �44.85 4.95 13.97 178.69 194.02 �5.81 1.75308.15 �49.89 �45.73 �17.53 14.44 105.00 195.26 �3.11 �1.75313.15 �50.27 �47.09 �26.34 �3.16 76.42 140.27 �0.23 �5.47318.15 �51.09 �47.42 �20.02 �40.07 97.65 23.08 2.85 �9.46

H2O–KCl 1.00 298.15 �52.92 �44.92 �69.30 �5.86 �54.96 130.98 5.50 0.26303.15 �52.42 �45.52 �40.53 �3.73 39.20 137.85 5.93 0.60308.15 �53.55 �46.65 �10.33 0.14 140.24 151.85 6.29 0.98313.15 �54.92 �47.60 22.23 5.99 246.38 171.13 6.58 1.37318.15 �55.75 �48.40 55.55 13.87 349.82 195.72 6.81 1.80

H2O–K2SO4 1.00 298.15 �50.47 �40.42 18.64 �23.03 231.81 58.31 �3.18 1.83303.15 �50.75 �41.25 4.81 �14.79 183.28 87.27 �3.22 2.03308.15 �53.77 �43.74 �13.74 �3.63 129.91 130.17 �3.26 2.24313.15 �51.69 �42.52 �29.64 9.57 70.41 166.34 �3.30 2.44318.15 �53.80 �43.65 �45.47 20.41 26.16 201.34 �3.33 2.62

a The error in the DG02;m values is in the range of ±0.06–0.15 kJ �mol�1.

b The error in the DH02;m values is in the range of ±0.25–2.0 kJ �mol�1.

c The error in the DS02;m values is in the range of ±1.6–3.5 J �mol�1 � K�1.

16 M.D. Hossain, M.A. Hoque / J. Chem. Thermodynamics 69 (2014) 12–18

increase of spontaneity of the micellization process with increasingtemperatures. For CDM–CDMEAB in water, the DH0

1;m values areinitially positive, the sign of DH0

1;m values alter from positive tonegative with elevation of temperature. The values of DS0

1;m are po-sitive and decrease gradually with increasing temperatures. Thusthe aggregation process in water is entropy controlled at lowertemperature and become both enthalpy and entropy controlledat higher temperatures. For (CDM + CDMEAB) system in water,

the DH02;m value is negative at T = 298.15 K, the sign of the DH0

2;m

values alter from negative to positive at middle range of studiedtemperatures and then the positive DH0

2;m value again change tonegative sign which enhances with further rise in temperatures.The positive values of DS0

2;m increase up to certain temperature,reach a maximum point and then tend to increase with furtherincrease of temperatures. Thus the CDM mediated CDMEABmicellization process is both enthalpy and entropy controlled at

0.05 0.10 0.15 0.20 0.25 0.30

-30

-20

-10

0

10

20

30

40

50

ΔH

0 1,m

/ ( k

J. m

ol-1

)

ΔS01,m / ( kJ.mol-1.K-1)

(a)

0.0 0.2 0.4-80

-60

-40

-20

0

20

40

60 (b)

ΔH0 1,

m /

( kJ. m

ol-1 )

ΔS01,m / ( kJ.mol-1.K-1)

-0.1 0.0 0.1 0.2 0.3 0.4 0.5

-80

-60

-40

-20

0

20

40

60

80

ΔH0 1,

m /

( kJ. m

ol-1

)

ΔS01,m / ( kJ.mol-1.K-1)

(c)

FIGURE 3. Enthalpy–entropy compensation plot for (CDM + CDMEAB) system (a) in water (0.9999), (b) in aqueous solution of KCl (0.9997), and (c) in aqueous solution ofK2SO4 (0.9987).

TABLE 7Enthalpy–entropy compensation parameters for (CDM + CDMEAB) system containing0.5258 mM CDM in water and in aqueous salt solution.

Medium I/mM DH0;�1;m/kJ �mol�1 DH0;�

2;m/kJ �mol�1 Tc,1/K Tc,2/K

H2O 0.00 �49.45 �47.17 303.15 316.30H2O–KCl 1.00 �52.78 �45.70 307.37 303.36H2O–K2SO4 1.00 �52.86 �41.49 310.00 304.50

M.D. Hossain, M.A. Hoque / J. Chem. Thermodynamics 69 (2014) 12–18 17

both lower and higher temperatures while that becomes entirelyentropy controlled at intermediate temperatures. The results re-veal that the binding interactions between CDM and CDMEAB areboth electrostatic and hydrophobic in nature while hydrophobiccontribution plays the crucial role. Both positive and negativeDH0

m values were also observed by Zielinski [29]. The positive val-ues of DH0

m at lower temperatures and negative values at highertemperatures was observed. The error in the calculation of DH0

m

values have been discussed by Emerson and Holtzer [30] and theyclaimed that a possible error in the in the calculation of DH0

m valuescould be as high as 2.0 kJ �mol�1.

In aqueous solution of KCl salt, initially the DH01;m values are neg-

ative, the values change to positive and then the positive values tendto increase with further increase of temperature. The values of DS0

1;m

is negative at 298.15 K, then sign of the values change to positiveand the positive values increase with increase of temperature. Thusthe behavior of drug-surfactant aggregation is both entropy andenthalpy controlled at lower temperatures whereas it becomes

almost entropy controlled at the elevated temperatures. Initiallythe DH0

2;m values are negative, the negative values decrease withtemperature, change to positive value and the positive value in-crease with further rise in temperature. The values of DS0

2;m are po-sitive and the positive values increase with increase of temperature.Thus the second micellization process is both entropy and enthalpycontrolled at lower temperatures and only entropy controlled atelevated temperature. The large values of DH0

m and DS0m indicate that

the enhanced hydrophobic interaction facilitate the process at high-er temperatures. In aqueous solution of K2SO4 salt, the DH0

1;m valuesare initially positive, the sign of DH0

1;m values change from positive tonegative and then the negative values increase with elevation oftemperature. The positive values of DS0

1;m decrease gradually withincreasing temperatures. Thus the aggregation process is entropydriven at lower temperatures whereas that becomes both entropyand enthalpy driven at higher temperatures. The DH0

2;m and DS02;m

values reveal that aggregation process is both entropy and enthalpydriven at lower temperatures whereas that it becomes entropy dri-ven at higher temperatures. The net DH0

m is the sum of the change inenthalpies arising from hydrophobic interactions, electrostaticinteractions and hydration of polar head groups. When the first ef-fect becomes dominant compared to combined effects of secondand third ones, the DH0

m values exhibit positive nature. A negativeDH0

m may arise when second and third effects become more effec-tive than the first one. The positive values of DS0

m for CDM mediatedsurfactant micelles can be explained considering two factors. Theseare: (1) shift of hydrophobic chains from hydrated form in aqueous

18 M.D. Hossain, M.A. Hoque / J. Chem. Thermodynamics 69 (2014) 12–18

medium to the nonpolar interior of the micelle and (2) increase offreedom of hydrophobic chains in the micelle interior comparedto the aqueous environment [31].

The molar heat capacity changes (DmC0p) for micelle formation

were obtained from the slope of the plot of DH0m vs. temperature

[32,33] using the following equation:

DmC0p ¼ @H0

m

� �=@T

� �p: ð4Þ

DmC0p is an important sign of protein structural changes in response

to different ligands [33]. The values of DmC01;p for (CDM + CDMEAB)

system in water are initially negative, the negative values decreaseand final change to positive with increasing temperature whereasfor DmC0

2;p are initially positive, change to negative and the negativevalues increase with increase of temperature. In the presence of KClsalt, the DmC0

p values are positive and the positive values increasewith increase of temperatures. For the presence of K2SO4 salt, theDmC0

1;p and DmC02;p values are negative and positive respectively

while the values increase with increase of temperature. A negativevalue of DmC0

p indicates that DH0m becomes more negative as the

temperature increases. The change in heat capacity associated withCDM–CDMEAB binding is believed to be associated with motionrestriction and is proportional to the funeral of the molecular sur-face, which generally draws a parallel with a change in the solventaccessible surface area [33]. However, the small DmC0

p and the over-all positive binding entropy indicate a slight structural rearrange-ment of CDMEAB micelle during binding with CDM.

The enthalpy–entropy compensation, a linear relationship be-tween DH0

m and DS0m with R2 value in the range of 0.995–0.999,

was obtained in all the cases (figure 3) according to the followingregression equation [34]:

DH0m ¼ DH0;�

m þ TcDS0m; ð5Þ

where the slope, Tc, the compensation temperature which charac-terizes the solute–solvent interactions i.e. the arrangement of watermolecules surrounding the micelles. Thus Tc values are consideredas a measure of the compensation and have been used as the basisof comparison for differing examples to observe compensationbehavior. The Tc value lying in the range (270 to 300) K has beenused as a pinpointing assay for the association of water in the pro-tein solution [35]. The intercept DH0;�

m is the intrinsic enthalpy gainwhich characterizes the CDM–CDMEAB interaction. The values ofDH0;�

m and Tc for (CDM + CDMEAB) system in pure water and in thepresence of salts are presented in table 7. The Tc,1 value for(CDM + CDMEAB) system in pure water is lower and Tc,2 valuesare higher than those of the presence of salts KCl and K2SO4. Forthe surfactant system entropy and enthalpy terms are set up to bal-ance each other both in pure water and also in the presence of salts.When the positive entropy term is reduced, its counterpart the en-thalpy term becomes increased to maintain the negative free energywhich was also observed by others for the micellization of ionic sur-factants in water [36]. The large negative DH0;�

m values reveal that

the CDM mediated CDMEAB micellization is favoured even at zeroentropy value. An increase in the negative DH0;�

m values resemblesto the buildup in the stability of the formation of the micelles.The negative DH0;�

m values also reveal that the CDM–CDMEAB aggre-gation is more preferable in salts solution whereas the CDM medi-ated CDMEAB micellization is more preferable in water.

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JCT 13-222