Effect of salts and temperature on the interaction of

Journal of Molecular Liquids 244 (2017) 512–520

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

Effect of salts and temperature on the interaction of levofloxacin hemihydrate drug with cetyltrimethylammonium bromide: Conductometric and molecular dynamics investigations Md. Anamul Hoque a,⁎, Md. Masud Alam a, Mohammad Robel Molla a, Shahed Rana a, Malik Abdul Rub b, Mohammad A. Halim c,d, Mohammed Abdullah Khan a, Anwar Ahmed e a

Department of Chemistry, Jahangirnagar University, Savar, Dhaka 1342, Bangladesh Chemistry Department, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia c Division of Quantum Chemistry, The Red-Green Computing Centre, BICCB, 218 Elephant Road, Dhaka 1205, Bangladesh d Institut Lumière Matière, Université Lyon 1 – CNRS, Université de Lyon, 69622 Villeurbanne, France e Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia b

a r t i c l e

i n f o

Article history: Received 27 June 2017 Received in revised form 31 August 2017 Accepted 1 September 2017 Available online 5 September 2017 Keywords: Levofloxacin hemihydrate (LFH) Critical micelle concentration (CMC) Thermodynamic parameters Stability Molecular dynamics simulation

a b s t r a c t Investigation of the interaction of the beta-lactum antibiotic drug levofloxacin hemihydrate (LFH) with cetyltrimethylammonium bromide (CTAB) has been performed in aqueous solution and in the attendance of salts at various temperatures (298.15, 303.15, 308.15, 313.15 and 318.15 K). A single critical micelle concentration (CMC) was observed for pure CTAB and their mixture with the drug (LFH). The CMC values for mixed systems (LFH + CTAB) in the presence of salt showed lower in magnitude in comparison to their absence. This pointed out the early micellization of the mixture of LFH and CTAB. All the ΔG0m values were found to be negative for all systems. The ΔH0m and ΔS0m values showed that hydrophobic and electrostatic interactions were boosted in the presence of salts compared to their absence at lower and higher temperatures respectively. The other thermodynamic parameters such as transfer energy (ΔG0m.tr.), transfer enthalpy (ΔH0m.tr.) as well as transfer entropy (ΔS0m.tr.) were also determined and discussed in detail. The intrinsic enthalpy gain (ΔH0,⁎m) and the compensation temperature (Tc) were also evaluated and discussed. Molecular dynamics simulation reveals that aqueous as well as salt environment have impact on the hydrophobic interaction between LFH and surfactant. © 2017 Elsevier B.V. All rights reserved.

1. Introduction The presence of both hydrophobic, as well as hydrophilic parts in an individual surfactant, is accountable to form aggregates in aqueous/ nonaqueous solution, termed as micelles and this phenomenon takes place beyond a certain surfactant concentration which is acknowledged as critical micelle concentration (CMC) [1–3]. The micelles of surfactant have been employed as a model of biological membranes. Appliances of surfactants are mainly dependent on the complex formation behavior of surfactants with solutes such as drugs, dyes, organic molecules etc. [1– 7]. In pharmaceutical industries, micelles are able to solubilize the feebly soluble organic compounds in aqueous solution by integrating them in the micellar phase [8,9]. Micelles have large surface area, therefore, they are suitably exploited to perform as catalysts for numerous chemical reactions, able to modify the reactions pathways, rates as well as equilibria [8,9].

⁎ Corresponding author. E-mail address: [email protected] (M.A. Hoque).

http://dx.doi.org/10.1016/j.molliq.2017.09.004 0167-7322/© 2017 Elsevier B.V. All rights reserved.

Amphiphiles mixed systems are sound reported in the previous study, being of key interest in order to advance their self-assembly and convenient applications [1,4–6,10,11]. Levofloxacin hemihydrate (LFH, Scheme 1), [(−)-(S)-9-fluoro-2,3-dihydro-3-methyl-10-(4methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6carboxylicacid hemihydrate]; is an advanced generation of fluoroquinolone antibiotic. LFH has been employed to cure diseases of the sinuses, skin, lungs, ears, bones as well as joints due to vulnerable microbes. Moreover, it is usually employed to cure pneumonia, urinary tract illness, and abdominal infections together with those opposing to other antibiotics and prostatitis. On the other hand, among a large number of conventional surfactant, we have chosen the cationic surfactant CTAB which have multipurpose uses such as removal ability of heavy metal from magnetic nanoparticles [5] and use as an adsorbent to remove of toxic and harmful compounds such as herbicides from the water. Even though a numerous investigation on the surfactants interaction through various molecules together with drugs are accounted earlier [3–6,10–17]. But to the best of our awareness, only some is documented on the interaction of LFH (drug) by means of CTAB using the

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2. Experimental section 2.1. Preparation of solutions

Scheme 1. Molecular structure of levofloxacin hemihydrate (LFH).

conductometric method. The study is of potential significance to gain insight into complex aggregation behavior of surfactant with drug both in absence and presence of salts. Furthermore, this study demonstrates that while designing such formulations one must consider the associated physicochemical changes which may affect the pharmacokinetic activity of drugs and the delivery properties of that formulations. In our earlier studies, the interaction of drugs with ionic surfactants in absence as well as in absence of different salts was accounted [14–18]. Recently, we also investigated the interaction of ciprofloxacin hydrochloride (CFH) with CTAB in presence of various electrolytes (NaCl, KCl, NH4Cl) [9]. For the further extension of our previous study, the interaction of LFH by means of CTAB (cationic surfactant) in absence and presence of NaCl, KCl, and NH4Cl was investigated via a conductometric method. The use of additives such as inorganic salts, drugs etc. is a familiar process to modify the micellization performance of amphiphiles. The presence of salts in amphiphiles reduces the electrostatic repulsion among the charged head group which decreases the critical micelle concentration (CMC). In addition, strong electrostatic interactions significantly influence the adsorption of amphiphile molecules at the interface of air and water [19,20]. Hence, it can be assumed that the degree of adsorption in the presence of salts should be considerably different in comparison to their absence in the surfactant solution. The various parameters such as critical micelle concentration (CMC), counter ion binding (β), thermodynamic parameters (ΔG0m, ΔH0m, and ΔS0m) related with the LFH and CTAB interaction in aqueous solution and in presence of salts have been estimated to illustrate the interaction behavior between LFH and CTAB.

The stock solutions of LFH (drug) and surfactant (absence or presence of a known concentration of NaCl, KCl, NH4Cl) were prepared using double de-ionized distilled water having the specific conductivity in the range of 1.5–2 μS cm−1. All the materials employed in the present study were used without additional purification. Cetyltrimethylammonium bromide CTAB (0.99 in mass fraction, CAS Registration No. 57-09-0) was purchased from Aldrich, USA. LFH as USP standard sample (0.98 in mass fraction, CAS Registration No. 138199-71-0, provided by the ACME Laboratories Ltd., BD), NaCl (0.995 in mass fraction, CAS Registration No. 7647-14-5, BDH, England), KCl (0.995 in mass fraction, CAS Registration No. 7447-40-7, BDH, England), and NH4Cl (0.995 in mass fraction, CAS Registration No. 12125-02-9, Merck, Germany) were used in this study. 2.2. Conductivity technique An aqueous solution 25 mmol L−1 CTAB prepared in water or (LFH + water), in absence or presence a known concentration of NaCl, KCl, NH4Cl; is gradually added to 20 mL of water or (LFH + water) solution of a particular drug (LFH) concentration (absence or presence a known concentration of NaCl, KCl, NH4Cl) at fixed temperature. After that, the specific conductance of the prepared mixtures was evaluated by means of a conductivity meter (model 4510, Jenway, UK) having a dip cell (glass electrode) of cell constant 0.97 cm− 1 [5–8,14–18,21,22]. This instrument was calibrated using solutions of KCl of the suitable range of concentration. An alternating current (AC) voltage source at a frequency of 60 Hz was applied for conductance measurements. The accuracy of the conductance measurements is in range of ±0.5%. The temperature of systems was controlled within the stated range by circulating water (RM6 Lauda thermostated water bath) throughout the solution having error of ± 0.2 K. To see the effect of salt, both the LFH as well as CTAB solutions are prepared in presence of NaCl, KCl, NH4Cl, therefore, all the solutions hold the same concentration of salt. 2.3. Molecular dynamics simulations Molecular dynamic (MD) simulation was performed on two systems containing surfactant-drug with water in presence of salt and without

Fig. 1. Specific conductance versus concentration of CTAB for (a) pure CTAB in water and (b) (LFM + CTAB) mixed system in water containing 1.032 mmol L−1 LFH at 303.15 K.

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Table 1 Physicochemical parameters for CTAB and (LFH + CTAB) systems in aqueous solution and different concentrations of LFH at 303.15 K.a Systems

CTAB (LFH + CTAB)

cdrugs

CMC

(mmol L−1)

(mmol L−1)

0 0.503 1.032 2.015 3.002

0.99 0.96 0.93 0.85 0.79

XCMC×105

α

ΔG0m

β

(kJ mol−1) 1.78 1.73 1.67 1.53 1.42

0.26 0.33 0.32 0.32 0.51

−47.87 −46.25 −46.64 −46.51 −46.88

0.73 0.67 0.68 0.68 0.69

a Relative standard uncertainties (ur) is ur(CMC) = ±3%, ur(α) = ±4%, ur(β) = ±4% and ur(ΔG°m) = ±3%.

salt. For surfactant, 32 molecules of CTAB were considered. The initial surfactant molecule was optimized by Universal Force Field [23] in Gaussian 09 Software package [24] then each surfactant molecular are paired up and clustered together through continuous minimization. Six drugs molecular are randomly placed in each system. For considering salt containing surfactant-drug system, 10 Na+, and 10 Cl− ions were added. All molecular dynamics simulations were conducted using NOVA force field in the suite of YASARA Dynamic program [25]. A cut-off radius of 8.0 Å was employed for short-range van der Waals as well as Coulomb interactions. The particle-mesh Ewald method [26] was applied to compute the long-range electrostatic interactions. Periodic boundary condition (cell box of 54 Å × 68 Å × 46 Å) and temperature of 298 °C were considered for all simulations. Time step of 1 fs was used and simulation snapshots were saved at every 100 ps. 2261 water molecules were added to keep the solvent density of 1 g/mL for both systems. A total of 17,008 atoms were present in those systems. The systems were minimized along with equilibrated with the default protocols of the YASARA dynamic. Lastly, 3 ns non-constrained MD simulation was executed for all system.

Fig. 2. Plot of XCMC versus T for (LFH + CTAB) mixed system containing 1.032 mmol L−1 LFH drug in water (■) and aqueous solution of 0.506 mmol L−1 (●), 1.098 mmol L−1 (▲), 2.038 mmol L−1 (▼) and 3.087 mmol L−1(◄) KCl. XCMC is in order of 10−5.

3. Result and discussion 3.1. Critical micelle concentration (CMC) as well as counter ion binding (β) In the current investigation, the values of critical micelle concentration (CMC) are evaluated by the observed change in specific conductance values versus the concentration of CTAB in water or LFH and water mixture. Fig.1 demonstrates the variation of specific conductance (κ) vs. concentration of surfactant (cCTAB) of pure CTAB in aqueous solution or (LFH + water) mixed system at 303.15 K. The conductivity value of solution changed linearly with the concentration of amphiphile in the pre and post-micellar regions. A clear break point in the κ versus cCTAB

Table 2 Physicochemical parameters for CTAB and (LFH + CTAB) system containing 1.032 mmol L−1 LFH drug in aqueous solution as well as in presence of different salts of different concentrations at fixed and various temperatures.a Systems

Medium

T (K)

CMC (mmol L−1)

XCMC ×105

α

β

1.01 0.99 1.05 1.16 1.23 1.33 0.95 0.93 1.00 1.06 1.16 0.93 0.83 0.70 0.60 0.60 0.84 0.77 0.70 0.64 0.86 0.80 0.74 0.68

1.82 1.78 1.89 2.09 2.21 2.39 1.71 1.67 1.80 1.91 2.09 1.67 1.49 1.35 1.21 1.08 1.51 1.39 1.26 1.15 1.55 1.44 1.33 1.22

0.27 0.28 0.29 0.30 0.30 0.31 0.31 0.30 0.34 0.35 0.37 0.30 0.31 0.29 0.29 0.28 0.31 0.31 0.29 0.28 0.31 0.32 0.27 0.26

0.73 0.72 0.71 0.70 0.70 0.69 0.69 0.68 0.66 0.65 0.63 0.68 0.69 0.71 0.71 0.72 0.69 0.69 0.71 0.72 0.69 0.68 0.73 0.74

−1

Csalts (mmol L CTAB

H2O

(LFH + CTAB)

H2O

(LFH + CTAB) (LFH + CTAB)

H2O (NaCl + H2O)

298.15 303.15 308.15 313.15 318.15 323.15 298.15 303.15 308.15 313.15 318.15 303.15 303.15

(LFH + CTAB)

(KCl + H2O)

303.15

(LFH + CTAB)

(NH4Cl + H2O)

303.15

a

) 0.00

0.00 0.00 0.00 0.00 0.00 0.00 0.505 1.067 2.035 3.013 0.506 1.078 2.038 3.087 0.507 1.035 2.009 3.003

Relative standard uncertainties (ur) is ur(CMC) = ±3%, ur(α) = ±4% and ur(β) = ±4%.

M.A. Hoque et al. / Journal of Molecular Liquids 244 (2017) 512–520

Fig. 3. ln (CMC/mmol L−1) versus T for (LFH + CTAB) mixed system in water.

plot was obtained in between pre and post-micellar region is regarded as the critical micelle concentration (CMC) and it is equivalent to the concentration of amphiphile corresponding to the break point [3,14– 18,27,28]. At low surfactant concentrations, the initial rise of specific conductance values were due to the involvements of the free CTA+ and Br− ions. However, above the CMC, the increase of specific conductance values becomes smaller due to the formation of CTAB micelles and also because of the condensation of the Br− ions with CTAB micelles to form Helmholtz layer. This stabilizes the self-micellized amphiphiles by means of surface charge neutralization and hence lowering intermolecular repulsion potential [29]. Therefore the formed micelles have poorer

Table 3 Values of thermodynamic parameters for pure CTAB and (LFH + CTAB) mixed system containing 1.032 mmol L−1 LFH in aqueous solution as well as in presence of NaCl.a System

CTAB

Medium

Isalt

H2O

0.00

(LFH + CTAB) H2O

0.00

(LFH + CTAB) (H2O + NaCl) 0.505

(CFH + CTAB) (H2O + NaCl) 1.067

(LFH + CTAB) (H2O + NaCl) 2.035

(LFH + CTAB) (H2O + NaCl) 3.012

T

ΔG0m

(K)

kJ mol−1 kJ mol−1 J mol−1 K−1

ΔH0m

298.15 303.15 308.15 313.15 318.15 323.15 298.15 303.15 308.15 313.15 318.15 298.15 303.15 308.15 313.15 318.15 298.15 303.15 308.15 313.15 318.15 298.15 303.15 308.15 313.15 318.15 298.15 303.15 308.15 313.15 318.15

−46.85 −47.41 −47.65 −47.70 −48.20 −48.31 −46.94 −46.64 −46.55 −46.79 −46.77 −46.84 −47.41 −47.79 −48.14 −48.49 −47.42 −48.45 −48.38 −48.77 −48.98 −48.17 −48.73 −49.16 −49.74 −49.85 −49.09 −49.49 −49.92 −50.17 −50.14

5.08 −1.59 −8.01 −13.10 −16.64 −22.01 6.24 −5.13 −13.13 −16.15 −20.63 8.18 −2.42 −19.11 −20.27 −24.34 10.18 −7.35 −20.55 −23.50 −28.00 12.19 −1.75 −22.03 −25.55 −30.50 16.64 1.31 −25.17 −27.68 −33.07

ΔS0m

174.19 151.13 128.63 110.49 99.19 81.39 175.22 136.92 108.74 97.85 82.18 184.52 148.43 93.07 89.00 75.92 193.19 135.58 90.31 80.71 65.95 202.45 154.98 88.02 77.25 60.81 220.45 167.59 80.32 71.83 53.66

a Relative standard uncertainties (ur) are ur(ΔG0m) = ±3%, ur(ΔH0m) = ±4% and ur(ΔS0m) = ±4%.

515

mobility compare to the free ions of CTAB. The literature showed that the value of CMC of pure CTAB in water at 303.15 K lies in the range of 0.8–1.1 mmol L−1 which is in fine agreement with our obtained values [4,11,8,18]. The degree of ionization (α) of micelles is evaluated from the ratio of the slopes of the pre and post-micellar regions related to the above as well as below CMC [4,14–18,21,22]. The value of α can be calculated from the ratios S2/S1, if S1 and S2 are the slopes above and below CMC. The fraction of counter ion binding, β, at CMC is evaluated by deducting the value of α from unity i.e. β = 1 − α. The values of critical micelle concentration (CMC) with its mole fractional values (XCMC), micelle ionization (α) and the fraction of counter ion binding (β) of pure surfactant and (LFH + CTAB) in H2O at 303.15 K are listed in Table 1. The CMC or XCMC values for (LFH + CTAB) mixed system in aqueous solution are lesser in magnitude in comparison to that of pure CTAB and the values of CMC reduce gradually with the increase of the concentrations of drug for (LFH + surfactant) mixed system at 303.15 K. This demonstrates the interaction between LFH and CTAB and reveals that the addition of LFH in the solution supports the formation of CTAB micelle. The values of CMC or XCMC, α and β for (LFH + surfactant) mixture at 303.15 K in the attendance of salts are shown in Table 2. The concentration of electrolytes in the body membranes may vary from time to time. The presence of various electrolyte and it's concentration may influence the interaction propensity of surfactant. Hence, it is essential to have awareness of aggregation phenomena for pure CTAB and LFH + CTAB mixtures by means of temperature together with in attendance of electrolytes. Herein, the values of CMC of (LFH + CTAB) mixture at 303.15 K in the presence of all the inorganic salt used in the present study are found to be lower in magnitude in comparison to salt-free solution. The CMC value of pure CTAB and their mixtures with CFH decreases in the presence of salt (Table 2). In case of ionic surfactants, as the inorganic salt added CMC decreases [4,27,28]. The values of CMC are also reduced with the increase of the ionic strength (concentration) of salts. This indicates that higher concentration of salts provides a convenient environment for micellization of our studied (LFH + CTAB) system. The co-ions for pure as well as mixed system micelles are Na+, K+, and NH+ 4 . The effect of salts on the decrease of CMC or XCMC values of mixed systems followed the order: CMCNaCl ˃ CMCKCl ˃ CMCNH4Cl (Table 2). This shows that NaCl is more effective in the reduction of CMC of the current studied system in comparison to KCl and NH4Cl. The change of CMC values possibly owing to the attendance of different cations in the salts keeping identical anion (Cl−). NH+ 4 is the least effectual in lessening the CMC owing to the small size along with bulky hydrated radius. Therefore this salt performs as a water-structure promoter, lessening the accessibility of H2O to the micelles. Similar behavior of these cations on the CMC values of ionic surfactant has also been reported earlier [4]. The values of CMC or XCMC, α, and β for pure CTAB and (CFH + CTAB) mixed system at various temperatures in aqueous solution are shown in Table 2. The CMC values or XCMC, α and β for (CFH + CTAB) mixed system at different temperatures in presence of salts are shown in Fig. 2 and Figs. S1 and S2 (Supporting information), as well as the corresponding data, also presented in Tables TS1–TS3 (Supporting information). For pure surfactant and (CFH + surfactant) mixture in H2O, the values of CMC or XCMC initially decrease and reaches to a minimum position and then increase with enhancing of temperatures. A nonlinear (curvature) behavior is found in the XCMC versus T plots (Fig. 2 and Fig. S1–S2 (Supporting information)). This behavior of nonlinearity/minimum position in the CMC versus T plots is also found in the literature for various other ionic surfactants in aqueous solution or in presence of different solutes [14]. The effect of temperature on the values of CMC can be clarified by means of the mode of hydration close to the monomers of CTAB and the LFH arbitrated micelles of CTAB. At low concentration of surfactant the monomeric form the hydrophobic as well as hydrophilic hydrations are feasible, while only hydrophilic hydration is feasible for assembled CTAB. All

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Fig. 4. Enthalpy-entropy compensation plot for (a) CTAB in H2O and (b) (LFH + CTAB) mixed system in aqueous medium.

kinds of hydrations are supposed to be reduced through the rise of temperature. A reduce in hydrophilic hydration promotes the micelle formation whereas a reduce of hydrophobic dehydration by means of the rising of temperature barred the formation of micelle [4,15,15]. Therefore, the extent of both features decides whether the values of CMC increase or decrease at a particular range of temperatures. Usually, the first factor dominates at lower temperature range and after an assured temperature, the second factor initiates governing. 3.2. Thermodynamics of micellization of mixed system The association process can also be analyzed using thermodynamic parameters. Different thermodynamic parameters for (LFH + CTAB) mixed system were evaluated by means of the following set of equations [14–18,29–33]: ΔG0 m ¼ ð1 þ βÞRT ln ðCMC Þ ΔH ∘m ¼ −ð1 þ βÞRT 2

ΔS∘m

¼

ð1Þ

  ∂ ln CMC ∂T

ð2Þ

  ΔH 0m −ΔG0m

ð3Þ

T

Table 4 Values of ΔH0,⁎m and Tc for (LFH + CTAB) mixed system containing 1.032 mmol L−1 LFH in absence and presence of salts.a Systems

Medium

csalts −1

(mmol L CTAB (LFH + CTAB) (LFH + CTAB)

H2O H2O (NaCl + H2O)

(LFH + CTAB)

(KCl + H2O)

(LFH + CTAB)

(NH4Cl + H2O)

a

)

0.00 0.00 0.505 1.067 2.035 3.012 0.506 1.078 2.038 3.087 0.507 1.035 2.009 3.003

Relative standard uncertainties (ur) is ur(ΔH0,⁎m) = ±4%.

ΔH0,⁎m

Tc

(kJ mol−1)

(K)

−45.07 −44.14 −46.98 −47.66 −48.74 −49.12 −46.64 −47.13 −47.16 −48.26 −46.03 −46.96 −47.52 −48.46

287.91 286.40 293.45 298.92 301.86 299.11 298.51 298.03 294.30 297.42 295.17 299.68 296.42 297.73

In the above equation CMC values are in utilized in mole fraction unit. ln(CMC) versus T plot (Fig. 3) is obtained to be nonlinear. The plots are employed to evaluate Δ H0m and slopes are drawn at every studied temperature that is regarded as equivalent to ∂ ln(CMC) / ∂ T [15,25,28]. The different thermodynamic parameters values for studied systems in aqueous solution are shown in Table 3 and Tables TS 4–TS5 (Supporting information). The Δ G0m values are found to be negative in case of pure CTAB along with LFH and CTAB mixtures. It is obvious from the tables that the values of ΔG0m for CTAB are achieved to be negative in absence as well as attendance of LFH indicating the micelles formation is spontaneous phenomena. By increasing of drug concentration in the mixtures of LFH and CTAB, ΔG0m is found to be gradually additional negative. This signifies that in the mixed systems micelle formation take place easily together with the process of micellization is more spontaneous for drug-CTAB mixtures than CTAB alone. In attendance of salt, the negative Δ G0m values are obtained to be additional negative signifying favorable association phenomena, whereas dynamic force for aggregation is considerably increased in presence of NaCl/KCl/ NH4Cl. The ΔH0m values for LFH + CTAB mixtures in aqueous solution are found to be positive at 298.15 K, however, at higher temperature, these values become negative and increased with increase in temperature in absence as well as attendance of salt. The ΔS0m values are found to be positive at all temperature and their value decreases with an increase of temperatures. Therefore ΔS0m and Δ H0m values show the aggregation phenomenon is entropically controlled at lower temperatures while it turns into entropy as well as enthalpy controlled at higher temperatures. The negative values of ΔH0m and positive Δ S0m values for LFH-surfactant mixed systems signify that besides hydrophobic, electrostatic interactions also take part a crucial role in the association of LFH. This occurs by means of surfactant during formation of LFH supported surfactant micelles at higher temperature [34]. The hydrophobic involvement reduces whereas the electrostatic interaction enhances by means of the rise of temperature, keeping the negative values of ΔG0m almost constant at every temperature employed in the present study. Similar behavior of ΔH0m is also obtained for numerous ionic surfactants earlier [35,36]. Nusselder and Engberts [37] proposed that it is the London-dispersion forces that are accountable in the micellar progression for negative enthalpy values. The positive values of ΔH0m at lower temperature are possibly due to damage of structured water molecules in the region of hydrophobic portions viewing the significance of hydrophobic interactions in the phenomenon of micelle formation. In the case of both single as well as mixed system, positive along with negative enthalpy values are also previously reported [38–41].

M.A. Hoque et al. / Journal of Molecular Liquids 244 (2017) 512–520

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Fig. 5. Molecular dynamics snapshots of (A) CTAB-drug complex without salt (B) CTAB-drug complex with salt over 1000 ps time.

Upon addition of salt in the solution, the negative Δ H0m values of (drug + CTAB) mixtures increased compared to the aqueous medium at higher temperatures. This indicates that enthalpy contribution on the micellization of (drug + surfactant) mixtures is increased in the attendance of salts as compared to in aqueous solution. The value of ΔS0m for pure CTAB and LFH + CTAB mixtures are obtained positive at every studied temperature in absence and occurrence of salt. However their value decreases by means of increase in temperature and the decrease of Δ S0m value is due to lowering of hydration of hydrophobic parts of amphiphiles. The magnitude of the positive values of Δ S0m for (LFH + CTAB) mixed systems in the attendance of salt is more in comparison to aqueous system at the lowest temperature. The positive values are obtained to be increased by means of the enhance of the salts concentration. The positive values of ΔS0m can be explained by the rupturing of iceberg structures surrounding the hydrophobic portions of surfactant monomer accompanied by the increased the randomness in the micelles core [42]. At higher temperature, the values of Δ S0m become lower in presence of salt in the aqueous solution. Also at lower temperatures, the positive values of ΔH0m are observed to be increased with the increase of the concentrations of salts. In presence of salts, the

higher positive values of both ΔS0m and Δ H0m at lower temperatures are a good indication of increased hydrophobic interactions between the hydrophobic chains of surfactant and interaction among the hydrophobic chain of drug and CTAB. The higher negative values of ΔH0m and relatively lower positive ΔS0m values at higher temperatures in presence of salts also pointed out those electrostatic interactions are more important in presence of salts in comparison to the salt-free solution. Besides temperature, NaCl, KCl & NH4Cl destroy hydrophobic hydration of surfactant monomers, therefore, much lower energy is needed for aggregation in presence of salts. The net value of Δ G0m is the summation of the enthalpic (Δ H0m) along with entropic (− T Δ S0m) involvements and this is exposed in Fig. S3 (Supporting information). In the mixed system of LFH and CTAB in aqueous solution, the contribution of Δ G0m reduces along with that of entropy enhance by means of the rise of temperatures. In presence of salt in the solution follow the more or less similar trend with few exceptions. The various energy transfers such as (free energy of transfer (ΔG0m.tr.), enthalpy of transfer (ΔH0m.tr.) as well as entropy of transfer (ΔS0m.tr.) of micelles from pure surfactant in aqueous solution to LFH

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Fig. 6. A surfactant-drug micelle system with surrounding water molecules generated by 1000 ps molecular dynamics simulation.

+ CTAB in aqueous system and (LFH + CTAB) in presence of salt are calculated by means of the following relations [43,44]:

From all the system used in the present study, we obtain a linear line between the plots of ΔH0m versus ΔS0m with regression coefficient (R2) values in the range of 0.990–0.999 which is familiar as entropy-enthalpy compensation (Fig. 4). Similar behavior is also previously obtained by others researchers in aqueous solution [47]. The negative intercept is the intrinsic enthalpy gain (ΔH0,⁎m) and the slope of the compensation plots is the compensation temperature (Tc). The intercept Δ H0⁎m disclose the solute-solute interaction. It stands for an index of the efficiency of the hydrophobic portion to contribute to the micelle growth. The ΔH0,⁎m and Tc values for pure CTAB as well as LFH-surfactant mixtures in aqueous solution along with in the attendance of salts are shown in Table 4. The Tc values for LFH + CTAB mixture both in absence and attendance of salts are obtained to be in the range of 286–302 K. The Tc values of any system in the range of 270–300 K means this system can be employed as an indicative test for the contribution of H2O in the protein solution [48]. Therefore, the obtained values of Tc in the current system are in fine conformity with the standard values of Tc for the biological fluid. The more negative values of Δ H0,⁎m signify that the association of surfactant, as well as drug-CTAB mixtures, are occurs even at ΔS0m = 0. The raise of the negative values of ΔH0,⁎m discloses the higher stability of the micelles formed in the solution. 3.3. Insights from molecular dynamics

ΔG0 m:tr: ¼ ΔG0 m: ðadditiveÞ–ΔG0 m: ðaqueousÞ

ð4Þ

ΔH 0 m:tr: ¼ ΔH 0 m: ðadditiveÞ–ΔH 0 m: ðaqueousÞ and

ð5Þ

ΔS0 m:tr: ¼ ΔS0 m: ðadditiveÞ−ΔS0 m: ðaqueousÞ

ð6Þ

The ΔG0m.tr., ΔH0m.tr. and ΔS0m.tr. values for LFH-surfactant mixtures in aqueous as well as in presence of salts are given in Tables ST6–ST8 (Supporting information). The ΔG0m.tr value for LFH + CTAB mixtures in presence of salt at concentrations is obtained to be negative whereas, in aqueous solution and lower concentrations of salt, the ΔG0m.tr value is observed to be positive. The values of ΔH0m.tr. and ΔS0m.tr. for LFH + CTAB mixtures in aqueous solution and in attendance of salts are obtained to be positive at lowest temperatures whereas the values are negative at higher temperatures. The negative values of ΔH0m.tr. are also accounted for the transport of salt and proteins from aqueous solution to a urea solution [45,46]. The negative value of ΔH0m.tr. pointed out that the move of the hydrophilic portion of CTAB from aqueous solution to the LFH (drug) as well as LFH and salt mixtures is exothermic process while similar phenomena for the hydrophobic group is an endothermic phenomenon.

The two systems with and without salt are presented in Fig. 5. Visual inspection reveals that at 10 ps both systems are almost same where drug molecules are away from the surfactant micelle. At 200 ps, nearly all drug molecules are appeared to be close to the micelle surface at salt (NaCl) environment compared to the non-salt system. A surfactant-drug micelle system with surrounding water molecules generated by 1000 ps molecular dynamics simulation is shown in Fig. 6. At 1000 ps, the system containing salt is more compact related to the system with no salt. However, in both cases, water cannot penetrate to the core of the micelle. After 1000 ps, the micelle remains unchanging during the course of the entire simulation. The surfactant head is projected outward while the hydrophobic tails are dipped inside. The shape of surfactant micelle is nearly spherical in the salt environment, as seen from the molecular surface (Fig. 7A). However, without salt environment, the molecular surface of the surfactant-drug complex is entirely spherical up to 1000 ps (Fig.7B). Drug molecules are mostly interacted with the polar head of the surfactant and remain at the outer surface as detected by a reddish patch. The superimposed images (Fig. 8) of salt (black) and no-salt (yellow) systems obtained by 1000 ps molecular dynamics calculation further confirmed that salt may promote the

Fig. 7. Molecular surface of the (A) micelle with salt (B) micelle without salt as detected at 1000 ps of MD snapshots.

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519

Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.molliq.2017.09.004. References

Fig. 8. Superimposed image of micelle with salt (black) and micelle without salt (yellow).

micelle formation as we also observed in the experimental results. In addition, in the salt environment, sodium ions (purple) are prone to interact with water molecules whereas Cl− (green) ion involved more with the polar amino head of the surfactant. 4. Conclusions This study describes the role of the variation of temperature as well as the concentration of drug (levofloxacin hemihydrate) on the micellization phenomenon of cationic surfactant CTAB in absence as well as attendance of salts. The addition of drug decreases CMC value of pure surfactant at a different temperature. The decrease of the CMC of the mixture of CTAB with the drug in presence of salts is also observed. The increase of the values of counter ion binding (β) with gradual increase of the concentration of various electrolytes supports the stability of micelles. Molecular dynamics simulation disclosed the fact that indeed salt environment promotes the micelle formation of the surfactant-drug complex compared to the no-salt environment. The all values of ΔG0m are found to be negative in case of every studied system showing the formations of micelle are spontaneous phenomena in different medium. The values of ΔH0m and ΔS0m values reveal that hydrophobic and electrostatic interactions are enhanced in presence of salts compared to those in water at lower and higher temperatures respectively. From Molecular dynamics simulation, the following observations are obtained: (i) salt promotes the micelle formation (ii) micelle adopts nearly spherical shape (iii) drugs interact with the outer-sphere of the micelle closed to the cationic head and (iv) micelle structure stays compressed over the simulation time. Acknowledgment This project was supported by King Saud University, Deanship of Scientific Research, College of Science Research Center.

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