A study of the interaction between a phenothiazine drug promazine hydrochloride with cationic surfactants

MOLLIQ-03946; No of Pages 7 Journal of Molecular Liquids xxx (2013) xxx–xxx

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Journal of Molecular Liquids journal homepage: www.elsevier.com/locate/molliq

3Q1

Kabir-ud-Din ⁎, Abbul Bashar Khan, Andleeb Z. Naqvi

4

Department of Chemistry, Aligarh Muslim University, Aligarh 202002, India

O

F

2

A study of the interaction between a phenothiazine drug promazine hydrochloride with cationic surfactants

1

a r t i c l e

i n f o

a b s t r a c t

Article history: Received 27 July 2011 Received in revised form 5 September 2013 Accepted 5 September 2013 Available online xxxx

P

A tensiometric study at 303.15 K was made to study the binary mixed systems of a phenothiazine drug promazine hydrochloride with six cationic surfactants (decyl-, dodecyl-, tetradecyl-, hexadecyltrimethylammonoium bromides, and cetylpyridinium bromide/chloride). Relevant parameters were evaluated by using the Regular Solution Theory and Motomura treatment for binary mixed systems. Clint's model was also used to explain the nonideal behavior of the systems. The synergistic behavior (i.e., non-ideal behavior) for binary mixtures is explained by the deviation of critical micelle concentration (cmc) from ideal critical micelle concenideal tration (cmc*), micellar mole fraction (Xm ), the values of interaction pa1 ) from ideal micellar mole fraction (X1 rameter (β) and activity coefficients (fi) (for both mixed micelles and mixed monolayer). The excess free energy (ΔGex) explains the stability of mixed micelles in comparison to micelles of pure drug; the stability decreases with the increase in alkyl chain length of the surfactant. Interfacial parameters, i.e., Gibbs surface excess (Γmax), minimum head group area at air/water interface (Amin), free energy of micellization (ΔGοm), and standard Gibbs energy of adsorption (ΔGοads) were also evaluated for the systems. © 2013 Published by Elsevier B.V.

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Keywords: Promazine hydrochloride Cationic surfactants Critical micelle concentration Interaction parameters Activity coefficients

T

6 7 8 9 10 11 13 12 14 15 16 17 18 19 20

R O

5

C

37 36

1. Introduction

39

The dual nature of amphiphilic compounds (because of the hydrophilic and hydrophobic parts) is the foundation of their relation to both external and internal interfaces in solutions. In recent years, studying the mixed amphiphilic systems is in vogue [1–4] owing to their better performance than the pure individual components. The nonideality of mixing may cause synergism in the properties of amphiphilic mixtures that may be exploited in many ways to their end use applications [5]. For example, in dermatological preparations, the surfactant mixture synergism can minimize the total surfactant monomer concentration, which, in turn, reduces skin irritation [6]. Micelles can only be used as drug carriers and not as targeting systems due to their labile nature, although evidences are there that suggest possibility to alter the biodistribution of a drug by administering it in a micellar solution [7]. A large number of drugs from many pharmacological groups of compounds exhibit typical colloidal behavior [8–10]. Phenothiaznes act on a wide range of receptors in the nervous system and have been found to be versatile anticholinergic and antihistamine compounds. The micellar mode of association and the discontinuity in the physicochemical properties of phenothiazine drugs in the aqueous solutions have been studied by several workers [11–13]. As mentioned earlier the mixed micellar systems have been widely

46 47 48 49 50 51 52 53 54 55 56 57 58

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R

44 45

N C O

42 43

U

40 41

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⁎ Corresponding author. Tel.: +91 571 2703515. E-mail address: [email protected] (Kabir-ud-Din).

21 22 23 24 25 26 27 28 29 30 31 32 33 35 34

studied, but mixtures of drug–cationic surfactant have been less frequently examined [14–16]. Here we used the surface tension measurements to determine the critical micelle concentration (cmc) of various drug–cationic surfactant binary systems wherein the effect of chain length and head group of n-alkyltrimethylammonium bromides and nalkylpyridinium halides on the physico-chemical properties of a phenothiazine drug promazine hydrochloride (PMZ) by was studied using the various solution and thermodynamic theories [17–24]. The effect of alkyl chain length on the toxicity and pharmacology of a series of C10– C20 has been studied in the female rat [25], and toxicity decreases with the increasing length of alkyl chain up to C16. Cetyltrimethylammonium bromide (CTAB) has also been found to be non-carcinogenic in rats [26]. Cationic (CTAB) and a nonionic (C12E23) reduced the degradation of several penicillins by the factor 4 to 12, while anionic surfactant (NaLS) increased the rate of degradation [27]. Meakin et al. [28] concluded that when CTAB increases the rate of hydrolysis, it is likely that the site of interaction is the surface, where the ester linkage would be in a region of high hydroxyl ion concentration. For mixed micellar solutions, the theoretical models rely on the equilibrium between micelles and monomers in solution. The phenomenon of mixed micelle formation described by the Clint's model [17] is used to estimate the deviation of mixed micellar systems from the ideal behavior. The extent of deviation from ideal behavior is quantified via the dimensionless interaction coefficient β, originally introduced by Holland and Rubingh [18]. The Motomura treatment [19] has been used to determine the composition of mixed micelles from the variation of experimental cmc values with the change in composition of binary surfactant mixtures.

0167-7322/$ – see front matter © 2013 Published by Elsevier B.V. http://dx.doi.org/10.1016/j.molliq.2013.09.003

Please cite this article as: Kabir-ud-Din, et al., J. Mol. Liq. (2013), http://dx.doi.org/10.1016/j.molliq.2013.09.003

59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86

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Kabir-ud-Din et al. / Journal of Molecular Liquids xxx (2013) xxx–xxx

87

2. Experimental

3. Theoretical approach

121

88

2.1. Materials

3.1. Composition of mixed films and micelles

122

89 90

The composition of mixed adsorbed layers and micelles differs from that of pure components because of their mutual interactions. Using Motomura theory, which is based on the Gibbs–Duhem equation [31–33], the composition of mixed micelles is determined by use of Eq. (1)

123 124

98

The phenothiazine drug promazine hydrochloride (PMZ) (≥98%, Sigma, USA, CAS registry no. 53-60-1) and cationic surfactants, i.e., decyltrimethylammonium bromide (≥98%, TCI, Japan), dodecyltrimethylammonium bromide (≥98%, TCI, Japan), tetradecyltrimethylammonium bromide (≥99%, Sigma, USA), cetyltrimethylammonium bromide (≥99%, Merck, Germany), cetylpyridinium bromide (≥99%, Merck, Germany), and cetylpyridinium chloride (98%, BDH, England) were used without further purification. The γ vs. logC plots of pure surfactants showed no minima which ascertained their purity. Their aqueous stock solutions were prepared in doubly distilled water.

99

2.2. Surface tension measurements

100

The ring detachment method (Du Noüy Tensiometer) was used to measure surface tension (γ). The ring used in the measurement was cleaned by washing with doubly distilled water followed by heating through alcohol flame. Different mole fractions of mixed systems were prepared from stock solutions of different concentrations of PMZ and cationic surfactants. The γ at each mole fraction was measured by successive addition of concentrated solution of the mixture in pure water at 303.15 K. In order to determine the values of critical micelle concentration (cmc), two linear fits were used for each of the isotherms. The first line was fitted to the interval of concentration characterized by linear decrease of the surface tension and the second one to the region of concentration with nearly constant surface tension. The cmc values were determined from the break point of the surface tension vs log C curves and accuracy on the individual surface tension reading is approximately ± 0.5mNm− 1. The cmc values agree well with the literature (Table 1). Further, in conformity to the observations of Mandal and Nair [29], we too obtained slightly lower cmc value for CPB than CPC. Seemingly, the higher counterion association of CPB (as the larger the hydrated radius of the counterion, the weaker is the degree of binding) [29,30] results in CPB micelles with more rigid surface.

107 108 109 110 111 112 113 114 115 116 117 118

t1:5 t1:6 t1:7 t1:8 t1:9 t1:10 t1:11 t1:12 t1:13 t1:14 t1:15 t1:16 t1:17 t1:18 t1:19 t1:20 t1:21 t1:22 t1:23

0 DeTAB 0.1 0.5 0.7 0.9 1 DTAB 0.1 0.5 0.7 0.9 1 TTAB 0.1 0.5 0.7 0.9 1

33

cmc* (mM)

5.90 29.5 34.5 38.9 57.0

34.45 41.80 46.79 53.14

15.0 14.0 12.0 11.7 13.8

28.97 19.46 16.72 14.65

6.9 5.0 4.1 3.8 2.7

15.55 4.99 3.73 2.97

ð1Þ

F

128 127

Where

0

α1 ¼

O

R O

and

νi αi ði ¼ 1; 2Þ ν1 α 1 þ ν2 α 2

129

ð2Þ 131 130

ð3Þ

In Eq. (1), Xm M,1 is the micellar mole fraction of the surfactant, vi is the number of ions dissociated by the ith component, and δ is the Kronecker delta which is equal to 1 for identical counterions and 0 for different counterions. By using Eqs. (2) & (3) and δ value, the Eq. (1) for PMZ–cationic surfactant systems reduces to
α α  ∂cmc0 m X M; 1 ¼ α 1 − 1 2 2cmc ∂α 1


α α  ∂C 0 ¼ α1 − 1 2 2C ∂α 1

135 136 137 138

! ð4Þ T;P

139 140 141

Similarly, for mixed adsorbed layer Eq. (1) modifies to

σ X M; 1

132 133 134

! ð5Þ T;P

where XσM,1 is the mole fraction of the surfactant in the mixed adsorbed 142 143 layer, C is concentration of the surfactant at γ = 49 mNm−1 and 144 0

C ¼ 2C 146 145

O

cmc (mM)

C

Mole fraction of surfactants

U

t1:4

126

ν 1;c ν 2 α 01 þ ν 2;d ν1 α 02

0

Table 1 Variation of critical micelle concentration (cmc) and ideal critical micelle concentration (cmc*) with mole fraction of surfactants.

N

t1:1 t1:2 t1:3

δν 1;c ν 2;d

cmc ¼ ðν1 α 1 þ ν2 α 2 Þcmc

R

119 120

1−

∂cmc0 =∂α 01

125



P

105 106

α 01 α 02 =cmc0

D

103 104

0

m

X M; 1 ¼ α 1 −




E

101 102




T

96 97

C

94 95

E

92 93

R

91

Mole fraction of surfactants

cmc (mM)

0 CTAB 0.1 0.5 0.7 0.9 1 CPB 0.1 0.5 0.7 0.9 1 CPC 0.1 0.5 0.7 0.9 1

33

cmc* (mM)

3.40 1.52 1.20 0.96 0.87

7.03 1.70 1.23 0.96

3.55 1.12 0.81 0.66 0.52

4.55 1.02 0.74 0.58

3.16 0.10 0.89 0.79 0.55

4.78 1.08 0.78 0.61

σ Fig. 1 (a–d) shows the variation of α1, Xm M,1 and α1, XM,1 with respect 0 0 m to cmc and C , respectively. In all the systems XM,1 and XσM,1 values are higher than the corresponding α1 values with respect to cmc0 and C0, except in the case of mixed micelles of the drug and DeTAB where XσM,1 values are lower than α1. It is also observed from Fig. 1 (a–d) that with the increase in alkyl chain length of the surfactant, the differσ ence of Xm M,1 and XM,1 values with α1 also increases. Variation of α1 and XσM,1 with cmc0 for drug–CPB (Fig. 1 (e)), shows the same pattern as in case of drug–CTAB mixed micelles but the decrease is more in cmc0 in case of the former. It suggests that despite of totally different molecular dynamics (spin lattice relaxation time, T1, values) [29] there is no significant effect of pyridinium head group if replaced by trimethylammonium head group of CTAB in the mixed micelles.

147 148

3.2. Interaction between molecules in mixed adsorbed film and micelle

160

The properties of ideal or nonideal behavior of mixed micelles of PMZ–cationic surfactants are investigated by the pseudo phase model. According to this model, micelles are considered to be macroscopic phase in equilibrium with a solution containing corresponding monomers. As such, the ideal cmc is related to individual cmc's by Eq. (6) [34]

161

1 cmc

¼

α1 cmc1

þ

ð1−α 1 Þ cmc2

Please cite this article as: Kabir-ud-Din, et al., J. Mol. Liq. (2013), http://dx.doi.org/10.1016/j.molliq.2013.09.003

ð6Þ

149 150 151 152 153 154 155 156 157 158 159

162 163 164 165

Kabir-ud-Din et al. / Journal of Molecular Liquids xxx (2013) xxx–xxx

a

3

b 0.08

0.030

0.06 0.05 0.04 o

0.03

, cmc

o

m

0.025

C0, cmc0 (mM)

C0, cmc0 (mM)

0.07

,C

o

m

,C

0.015

o

XM,1 , C

o

XM,1 , C

0.01

cmc

XM,1 , cmc

XM,1 , cmc

0.02

o

0.020

o

o

0.010

0.00 0.2

0.4

0.6

0.8

1.0

0.0

0.2

0.4

m

0.8

1.0

m

, XM,1 , XM,1

c

O

, XM,1 , XM,1

d 0.014

cmc

o

m

XM,1 , cmc ,C

0.011

0.006

o

XM,1 , C

o

C0, cmc0 (mM)

0.012

0.010 0.009 0.008 0.007

0.004 0.003

o

m

,C

o

XM,1 , C

o

D

0.006

0.005

o

cmc

XM,1 , cmc

P

0.013

R O

0.007

o

C0, cmc0 (mM)

0.6

F

0.0

0.002

0.005 0.004

E

0.001

0.003 0.0

0.2

0.4

0.6

0.8

1.0

m

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

m

, XM,1 , XM,1

E

o

, cmc m

o

R

XM,1 , cmc

0.005

0.004

0.003

0.002

0.001 0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

1.1

, XM,1

U

N C O

0

R

cmc (mM)

0.006

0.2

C

e 0.008 0.007

0.1

T

, XM,1 , XM,1

Fig. 1. Variation of C0 (▲), cmc0 (■) with α1, C0 (Δ) with XσM,1, and cmc0 (□) with Xm M,1 for (a) PMZ–DeTAB, (b) PMZ–DTAB, (c) PMZ–TTAB, (d) PMZ–CTAB, and (e) PMZ–CPB binary mixed systems.

167 166 168 169 170 171 172 173 174 175 176 177

where α1, cmc *, cmc1, and cmc2 are the mole fraction of surfactant in the bulk, ideal cmc of mixture, cmc of pure surfactant, and cmc of drug, respectively. The experimentally obtained cmc values for pure and binary mixtures of the drug and surfactants as a function of mole fraction of surfactants are given in Table 1. A comparison of experimental cmc and cmc* values for the drug– surfactant binary mixtures shows that for DeTAB, DTAB and lower mole fraction (i.e., α1 = 0.1 & 0.5) of rest of surfactants (i.e. TTAB, CTAB, CPB and CPC), the cmc is lower than cmc* but, at higher mole fractions (i.e., α1 = 0.7 & 0.9) cmc is almost similar to cmc* for CTAB and higher than cmc for the rest of the surfactants. It depicts that with the increase in

the alkyl chain length and mole fraction of surfactants the nonideality decreases, and there is no noteworthy effect of head group and counterions. The standard free energy of micellization, ΔG°m, can be evaluated from the following equation ΔGBm ¼ RT lnX cmc

179 180 181

ð7Þ

where Xcmc is the value of cmc in mole fraction units. All the values of ΔG°m are negative indicating that the process of micelle formation is spontaneous. The general trend is that ΔG°m values for drug–surfactant mixtures are more negative than the values for pure

Please cite this article as: Kabir-ud-Din, et al., J. Mol. Liq. (2013), http://dx.doi.org/10.1016/j.molliq.2013.09.003

178

183 182 184 185 186

193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209

ideal

X1

¼

α 1 cmc2 α 1 cmc2 þ ð1−α 1 Þcmc1

ð8Þ

F

191 192

ideal The deviation of Xm values also en1 from the corresponding X1 ideal lightens nonideality in the mixed micelles. The Xm values 1 close to X1 m is a sign of ideal mixing, and higher X1 than the corresponding Xideal 1 points out that the mixed micelles are rich in surfactant, while higher ideal Xm indicates that mixed micelles are rich in 1 than corresponding X1 drug. From Table 2 it is clear that at two initial mole fractions, the Xm 1 value is higher than the corresponding Xideal , while in case of DTAB for α1 = 1 ideal 0.1, the Xm . For TTAB and 1 value is higher than the corresponding X1 m CTAB, at all mole fractions, X1 values are lower than the corresponding Xideal . Generally, at a particular mole fraction of surfactant the Xm 1 1 value increases with the increase in alkyl chain length of the surfactant. But comparing the CPB and CPC values at α1 = 0.1, the Xm 1 value is lower for CPC which further decreases on increasing the mole fraction. These results depict that nonideality decreases with the increase in alkyl chain length and with the increase in mole fraction of the surfactants and, on changing the head group, nonideality decreases but, on changing the counterion, significant effect is observed. m The values of fm 1 and f2 are in all cases less than unity, indicating nonideality. However, at high mole fractions of CTAB and TTAB, the values of fm 1 approach unity which indicates ideality in the system. The excess free energy of mixing, ΔGex, can be calculated using Xm i and fm i by the following equation [39]:

O

189 190

components. This shows that the process of micellization is more favorable for drug–surfactant mixtures than for pure amphiphiles. With the help of the Rubingh's procedure, which is based on RST [35], a quantitative interpretation of micellar mole fraction can be obtained [36,37]. The values evaluated are used for the calculation of the interaction parameter of mixed micelles, βm. The mixed micelle formation, due to the attractive and repulsive interactions are indicated by negative and positive βm values, respectively, while a value close to zero refers to an ideal behavior [38]. The above procedure not only characterizes the interaction parameter βm of the mixed micelles but also explains the deviation from ideality. The negative values of βm mean that the attractive interaction between drug and surfactant is stronger than the individual components. The activity coefficients (fm i ) in the mixed micelles were calculated according to the RST. For synergism in the mixed micelle formation, two conditions must be followed: (1) βm must be negative, and (2) βm N ln(cmc1/cmc2) [38]. For all surfactants and at all mole fractions, the first condition of synergism is met. The second condition is followed by DeTAB, DTAB and TTAB only. With other surfactants, the systems behave ideally and hence second condition is not met. In ideal state, the micellar mole fraction, was calculated by the equation [38]

R O

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Kabir-ud-Din et al. / Journal of Molecular Liquids xxx (2013) xxx–xxx

P

4

 m m m m ΔGex ¼ RT X 1 ln f 1 þ X 2 ln f 2

D

CTAB 0.1 0.5 0.7 0.9 1 CPB 0.1 0.5 0.7 0.9 1 CPC 0.1 0.5 0.7 0.9 1

C

0.55

−5.55 −0.89 −0.77 −0.91

−20.70 −20.87 −21.26 −21.32 −20.91

−3.11 −1.47 −1.91 −2.38

0.29 0.81 0.85 0.93

0.65 0.56 0.38 0.20

0.87

−1.83 −0.87 −0.98 −0.88

0.576 0.924 0.977 0.991

−22.65 −23.47 −23.97 −24.16 −25.02

−3.28

0.48

0.40

2.50

−2.06

0.630 0.893 0.967

0.808 0.974 0.989 0.997

−24.44 −26.46 −27.06 −27.62 −27.87

−3.48 −1.94 −1.20

0.62 0.98 0.99

0.25 0.21 0.32

3.64

−2.05 −0.47 −0.10

0.754

0.876 0.984 0.993 0.998

−24.33 −27.23 −28.05 −28.57 −29.17

−1.64

0.91

0.39

4.15

−0.78

0.708 0.920

0.869 0.984 0.993 0.998

−24.62 −33.32 −27.81 −28.11 −29.03

−2.44 −1.97

0.81 0.99

0.29 0.19

4.09

−1.27 −0.36

0.210 0.705 0.848 0.956

C

0.529

R

0.372 0.624 0.713 0.823

E

0.26 0.77 0.69 0.41

N

TTAB 0.1 0.5 0.7 0.9 1

0.03 0.61 0.78 0.86

0.060 0.367 0.575 0.839

R

DTAB 0.1 0.5 0.7 0.9 1

−18.71 −23.05 −19.00 −18.60 −18.30 −17.34

−9.36 −1.46 −1.24 −1.77

0.380 0.421 0.546 0.711

O

DeTAB 0 0.1 0.5 0.7 0.9 1

T

E

Table 2 ideal Micellar mole fraction of surfactants (Xm ), standard Gibb's energy of micellization (ΔG∘m), interaction parameter in mixed micelle (βm), 1 ), ideal micellar mole fraction of surfactants (X1 activity coefficients in mixed micelle (fm i ), and excess free energy of mixing (ΔGex). 
  1  ΔGex (kJ mol−1) Xideal ΔG0m (kJ mol−1) βm f1m f2m Mole fraction of surfactants Xm  ln cmc 1 1 cmc2 

U

t2:4 t2:5 t2:6 t2:7 t2:8 t2:9 t2:10 t2:11 t2:12 t2:13 t2:14 t2:15 t2:16 t2:17 t2:18 t2:19 t2:20 t2:21 t2:22 t2:23 t2:24 t2:25 t2:26 t2:27 t2:28 t2:29 t2:30 t2:31 t2:32 t2:33 t2:34 t2:35 t2:36 t2:37 t2:38 t2:39 t2:40 t2:41 t2:42 t2:43 t2:44 t2:45 t2:46

Please cite this article as: Kabir-ud-Din, et al., J. Mol. Liq. (2013), http://dx.doi.org/10.1016/j.molliq.2013.09.003

214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234

ð9Þ 235 236

211 210 t2:1 t2:2 t2:3

212 213

Kabir-ud-Din et al. / Journal of Molecular Liquids xxx (2013) xxx–xxx

244 245 246

 σ 2 σ X1 ln concα 1 =conc1 X 1    ¼ 1 2 1−X σ1 ln concð1−α 1 Þ=conc2 1−X σ1

18 16 14 12





20

10

ð10Þ

8 0.2

0.6

0.8

O

R O

Fig. 2. Variation of Γmax with the mole fraction of surfactants (α1).

260

3.3. Interfacial parameters

D

P

An effective measure of the adsorption at the air/water interface is 261 measured by the surface excess, Γmax, calculated by the Gibb's adsorp- 262 tion equation [38]: 263 
 1 ∂γ −2 ð11Þ Γ max ¼ − mol m 2:303nRT ∂ logC

Table 3 Mole fraction of surfactants in mixed monolayer (Xσ1 ), interaction parameter in mixed monolayer (βσ), activity coefficients in mixed monolayer (fσ i ), standard Gibb's energy change of adsorption at interface (ΔG∘ads), and molar free energy of maximum adsorption attained at the cmc (Gmin). 
  1  ΔG0ads (kJ mol−1) βσ f1σ f2σ Gmin (kJ mol−1) Mole fraction of surfactants Xσ1  ln conc conc2 

E

t3:4 t3:5 t3:6 t3:7 t3:8 t3:9 t3:10 t3:11 t3:12 t3:13 t3:14 t3:15 t3:16 t3:17 t3:18 t3:19 t3:20 t3:21 t3:22 t3:23 t3:24 t3:25 t3:26 t3:27 t3:28 t3:29 t3:30 t3:31 t3:32 t3:33 t3:34 t3:35 t3:36 t3:37 t3:38 t3:39 t3:40 t3:41 t3:42 t3:43 t3:44 t3:45 t3:46

0.4

Mole fraction of surfactants ( )

T

t3:1 t3:2 t3:3

DeTAB 0 0.1 0.5 0.7 0.9 1 DTAB 0.1 0.5 0.7 0.9 1 TTAB 0.1 0.5 0.7 0.9 1 CTAB 0.1 0.5 0.7 0.9 1 CPB 0.1 0.5 0.7 0.9 1 CPC 0.1 0.5 0.7 0.9 1

0.423 0.547 0.698 0.810

−10.41 −0.90 −0.72 −1.65

0.437 0.646 0.780 0.845

−32.92 −56.35 −41.47 −40.26 −38.07 −32.66

29.87 44.29 23.35 24.99 20.84 16.41

1.68

−46.53 −52.91 −51.64 −49.78 −35.84

39.89 35.82 32.31 30.93 15.02

3.48

−57.20 −47.36 −46.66 −43.37 −40.39

51.59 26.65 26.61 21.27 17.67

0.137

4.72

−41.93 −48.84 −49.73 −52.87 −47.11

24.03 22.43 23.94 28.09 22.73

0.788 0.995

0.129 0.124

5.1

−60.98 −56.37 −53.68 −51.75 −45.79

42.92 33.59 30.85 30.92 17.13

0.782 0.994

0.106 0.095

5.3

−55.31 −62.36 −53.14 −56.03 −60.33

36.98 35.80 32.36 38.27 44.01

C

258 259

0.031 0.832 0.936 0.942

0.156 0.764 0.703 0.338

0.27

−2.12 −3.71 −2.25 −3.18

0.511 0.628 0.897 0.926

0.667 0.213 0.254 0.104

0.600

−4.39

0.495

0.206

0.793

−5.08

0.805

0.041

0.707

−3.98

0.710

0.746 0.953

−3.69 −2.30

0.751 0.952

−3.97 −2.60

E

256 257

R

254 255

R

252 253

N C O

250 251

where conc, conc1, and conc2, are the concentrations of mixed micelles, surfactant and drug, respectively, at a definite surface tension (in our case, at 49 mNm−1). Other surface parameters similar to those for mixed micelles were calculated using Xσ1 values [34,35]. Table 3 shows that Xσ1 values are higher than the corresponding Xm 1 values, indicating that surfactants are rich in mixed monolayer as in mixed micelles due to more repulsion between drug and surfactants and its value increases with the increase in alkyl chain length of the surfactant. Furthermore, there is somehow increase in Xσ1 values at α1 = 0.1 for CPB in comparison to CTAB but almost there is no change in between CPB and CPC, which explains very less effect of head group and no effect of the counterion.

U

247 248 249

F

243

DeTAB DTAB TTAB CTAB CPB CPC

22 -2

241 242

24

7

239 240

All the negative ΔGex values show that the drug–surfactant mixed micelles are more stable than the micelles of pure components, but the stability decreases with increase in the chain length of surfactant, with the exception of DTAB, which gives most stable mixed micelles. The nature and the composition of the adsorbed monolayer can be evaluated by the extrapolated form of the mixed micellar regular solution theory. The molecules prefer to adsorb at the air/water interface rather than to aggregate, due to large and rigid hydrophobic portion [40]. The values of Xσ1 and βσ can calculated at a constant γ value by the following equation [41]:

max. 10 (mol.m )

237 238

5

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DeTAB DTAB TTAB CTAB CPB CPC

140 120 100

60 0.2

0.4

0.6

0.8

Fig. 3. Variation of Amin with the mole fraction of surfactants (α1).

and the minimum area per molecule, Amin, by the following equation [38]:

A min

274 275 276 277 278 279

O

C

288

∘

∘

ΔGads ¼ ΔGm −

290 289 291 292 293 294 295 296 297 298 299 300 301

πcmc Γ max

N

286 287

Gmin is the minimum free energy of the given surface with fully adsorbed amphiphile molecules. Lower the value of the free energy, more stable is the surface formed. Generally, Gmin value decreases with the increase in mole fraction of surfactant except in for CTAB where Gmin value increases. The standard Gibbs energy of adsorption, ΔG○ads, is evaluated by using [43]

U

284 285

ð13Þ

R

G min ¼ γcmc A min N A 281 280 282 283

308

Acknowledgments

325

ð14Þ

where πcmc (=γ0 − γcmc) is the surface pressure at the cmc, and γ0 and γcmc are the surface tensions of pure solvent and of the amphiphilic solutions at the cmc, respectively. Table 3 also shows that the ΔGοads value for all the systems is more negative than ΔGοm, which means that the process of adsorption at the surface is more favorable than the micelle formation. The hydrophobicity of the amphiphiles primarily leads them toward the air/water interface and then micelle formation takes place above the cmc, which is secondary and less spontaneous. The ΔGοads values decrease with the increase in the mole fraction of surfactant for all the systems except for CTAB. In case of CTAB, ΔGοads value increases with the increase in mole fraction CTAB.

305 306 307

309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324

A. Z. Naqvi acknowledges financial assistance under DST's SERC 326 Scheme (SR/FTP/CS-49/2007) and Abbul Bashar Khan is thankful to 327 UGC for fellowship. 328

T

272 273

where R, T, and NA are gas constant, temperature (in Kelvin), and Avogadro's number. n is introduced to allow for simultaneous adsorption of cation and anion. The value of n is used as 2 for pure drug and surfactants. The values of Γmax and Amin for mixtures are based upon n = 3 with the understanding that they merely indicate changes with the change in nature of mole fraction of additives. Figs. 2 and 3 show that the Γmax value increases and Amin value decreases with the increase in mole fraction of the surfactants except for CTAB. In case of CTAB, Γmax value decreases and Amin value increases with the increase in the mole fraction of CTAB. The molar free energy at the maximum adsorption attained at cmc, Gmin, is calculated using equation [42]:

C

270 271

ð12Þ

E

267 268 269

20
 10 2 ¼ ) N A Γ max

R

266

σ 1. For all PMZ–cationic surfactant systems, Xm M,1 and XM,1 values are higher than the corresponding α1 value with respect to cmc0 and C0, except in the case of mixed micelles of PMZ and DeTAB where Xm M,1 values are lower than α1. It is also observed that with the increase in alkyl chain length of surfactants the difference of Xm M,1 and XσM,1 values with α1 increases. 2. With the increase in the alkyl chain length and mole fraction of surfactants the nonideality decreases, and there is no noteworthy effect of head group and counterions of surfactants. 3. The Xσ1 values are higher than the corresponding Xm 1 values, indicating that surfactants are rich in mixed monolayer than in mixed micelles due to more repulsion between drug and surfactants and its value increases with the increase in alkyl chain length of surfactants. 4. The excess free energy (ΔGοex) values also explain the stability of binary mixtures as compared to pure drug micelles. 5. The higher values of ΔGοads than ΔGοm suggest that the process of adsorption at the surface is more favorable than the micelle formation.

O

Mole fraction of surfactants ( )

265 264

303 304

F

80

The surface and micellar properties of a binary drug (PMZ) and cationic surfactants (DeTAB, DTAB, TTAB, CTAB, CPB, and CPC) mixed systems have been studied by tensiometery. The drug forms mixed micelles with the cationic surfactants and following conclusions are obtained from the above discussion:

R O

A min (Å2)

160

302

P

180

4. Conclusion

D

200

E

6

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329

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U

N C O

R

R

E

C

T

E

D

P

R O

O

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389

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380 381 382 383 384 385 386 387 388