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Binary Mixtures of Sodium Salt of Ibuprofen and Selected Bile Salts: Interface, Micellar, Thermodynamic, and Spectroscopic Study Malik Abdul Rub,*,†,‡ Naved Azum,†,‡ and Abdullah M. Asiri†,‡ †

Chemistry Department, Faculty of Science, and ‡Center of Excellence for Advanced Materials Research, King Abdulaziz University, Jeddah, 21589, Saudi Arabia S Supporting Information *

ABSTRACT: With the intention to explore bile salts applications as drug delivery vehicles, the mixed interfacial as well as micellar behavior of the sodium salt of ibuprofen (NaIbuF) and bile salts mixtures in aqueous/electrolyte solutions has been evaluated by tensiometric method at 298.15 K. Bile salts (sodium cholate (NaC) and sodium deoxycholate (NaDC)) used in the present study are anionic in nature and form small micelles. Various theoretical models such as Clint, Rubingh, and Rosen were utilized to acquire information concerning the nature of interaction among the components in the solution as well as at the interface. Because of the presence of inorganic salt (100 mmol·kg−1 NaCl) a decrease in the surface charge of the micelles takes place and ensuing micellization occurs at poorer concentration. The value of the micellar mole fraction (Xm 1 ) is found to be greater for NaIbuF + NaDC mixtures in comparison to NaIbuF + NaC mixtures, signifying that participation of NaDC is greater in mixed micelles as compared to NaC. An attractive interaction was obtained in the micelle and at the interface, because it is obvious from interaction parameters (βm, βσ). The values of ΔG0m for all systems was negative in the absence as well as in the occurrence of salt. Micelle aggregation number (Nagg), estimated by means of steady-state fluorescence quenching studies, suggests that the contribution of bile salts was always greater than that of the NaIbuF. The micropolarity (I1/I3), Stern−Volmer binding constants (Ksv), and dielectric constant (Dexp) of mixtures also supported the synergistic behavior of the drug−bile salts mixed systems.

1. INTRODUCTION The inclusion of several compounds into a particular system allocates formation of mixed micelles with simple adjustable properties and purposes that, by composition deviation, are outstandingly diverse from those of the single compound micelles.1−6 If there are adequate synergistic interactions between components of mixed micelles, it means that mixed micelle formation is thermodynamically more stable, and therefore the critical micellar concentration (cmc) of the mixed amphiphiles systems must be lower than the cmc of the hydrophobic component.1−8 Numerous amphiphiles are capable of associating to form a specific structure called micelles; bile salts such as sodium cholate (NaC) and sodium deoxycholate (NaDC) participate in a significant function because they are biosurfactants in living things and principal cholesterol final products (fat digestion). Owing to their rigid steroidal configuration having hydrophobic as well as hydrophilic faces, their association behavior and micellar shape is dissimilar from the conventional surfactants. In aqueous solutions, the salt of bile acids forms small size micelles as compared to the traditional surfactants.9 The micelle shapes of bile salt, as well as the method of micellization, are still in question. Two key models have been suggested in the earlier work. Small proposed a model10 in which primary associates of bile salts are obtained by hydrophobic interactions, © 2017 American Chemical Society

whereas secondary associates appeared by means of intermolecular hydrogen bonding among the hydroxyl groups. The cmc of sodium salts of bile acids have usually been determined by the surface tension method in addition to many other methods also such as fluorescence, dye solubilization, microcalorimetry, conductimetry, nuclear magnetic resonance, potentiometry, etc.11−13 Sodium salts of bile acids contain carboxylate ion (−COO−) and hydroxyl (−OH) groups as the hydrophilic portion together with a steroid ring system. If the steroid skeleton contains alpha axial or alpha pseudoaxial OH groups then the beta side (convex surface of the steroid skeleton) is a hydrophobic part, whereas the alpha side (concave surface) is the hydrophilic part of the molecule, therefore hydrophobic and hydrophilic surfaces are completely separated from each other.13 But if the steroid skeleton contains an alpha or beta equatorial OH group or an oxo group then the beta side steroid skeleton becomes partially hydrophilic; therefore, their micelles are produced by hydrophobic interaction and subsequently hydrogen bonding.14 Bile salts take part in the function of digestion of animal fat as well as in various supplementary natural activities. Bile salts are broadly Received: March 29, 2017 Accepted: July 27, 2017 Published: August 11, 2017 3216

DOI: 10.1021/acs.jced.7b00298 J. Chem. Eng. Data 2017, 62, 3216−3228

Journal of Chemical & Engineering Data

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of mixed systems of amphiphiles. A precise knowledge of these quantities is important for their application modes which have been determined using of tensiometry technique. The pyrene (Py) fluorescence method has been used as complementary techniques for the fundamental understanding of the molecular structure of drug additives aggregates.21−23 In an aqueous solution, the salt effect on the cmc of a pure species as well as a mixed species system can be clarified chiefly by the salting-out effect of the hydrophobic part of amphiphiles.24,25 With the addition of NaCl, electrostatic repulsion among the amphiphile head groups is decreased, which is a chief issue in the control of the morphology of the associates’ structure of the charged amphiphiles, and this causes the decrease in the cmc of the amphiphiles. Bile salt is recognized to increase the penetration of different drugs across biological membranes.26 Therefore, it is visualized that mixed micelles formed by drug and bile salts mixtures would be suitable for pharmaceutical use. In addition, the formation of mixed NaIbuF and bile salts solutions is very simple because they are freely soluble in water. Hence, the main objectives of the current study are to reveal the characteristics of the bile salts micelles and to judge the capability of bile salts micelles to integrate the charged amphiphilic drug.

employed as carriers for hydrophobic drugs and enzymes, etc.10,15,16 Most pharmaceutical compounds have low water solubility which leads to poor absorption and loss in metabolism and excretion.17 Hence high concentration is needed. However, as some drugs are known to be toxic and have other side effects, high concentration may lead to high toxicity. Their mixed micelles with bile salts would increase their aqueous solubility and, as a result, a low concentration would be required. Ibuprofen (isobutylphenylpropanoic acid), is a medicine that falls in the class of nonsteroidal anti-inflammatory drug (NSAID) employed for the relief of pain and fever as well as swelling.18 This drug has a number of harmful formulation properties for example poor H2O solubility (below 1 mg/mL at 298.15 K) as well as a a low melting point (350.15 K).19 These troubles can be simply defeated by employing an (R,S)(±)-ibuprofen sodium salt (Scheme 1), which is highly soluble Scheme 1. Molecular Model of Sodium Salt of Ibuprofen (NaIbuF)

2. EXPERIMENTAL SECTION 2.1. Materials. All chemicals were of analytical grade and employed as obtained without further purification. Important information on the resource and purity of the employed chemicals are revealed in Table 1. All the chemicals were dried in a vacuum oven and kept in vacuum desiccators in the attendance of P2O5 as a very good water absorbent for more than 2 days before their use. The water content was evaluated by the Karl Fischer method and was obtained to be less than 100 ppm. This analysis was done in the current study with Karl Fischer titration (Metrohm, 701 KF Titrino, Switzerland). Deionized double distilled water (DDW) having specific conductivity (1 to 6)·10−6 S cm−1 was consumed throughout the study to prepare the stock solution. Drug (NaIbuF) and bile salts (NaC/NaDC) solutions were prepared by the combination of accurately measured volumes of amphiphiles in the absence/attendance of salt (NaCl). 2.2. Method. 2.2.1. Surface Tension Measurements. A tensiometer (Attension, Sigma 701, Germany) was employed to find surface tension (γ) via the ring detachment technique at 298.15 K. A detailed process was earlier reported.27 This instrument has an autocalibrating microbalance that assesses over a broad range. The calibration process was done with DDW daily prior to any solution measurements. The γ of pure amphiphiles, as well as their mixtures, was estimated by repeated addition of the solution in distilled H2O/in the attendance of NaCl (100 mmol·kg−1). The cmc values of pure species and their mixtures were obtained from the inflection point in the curve of the γ vs logarithm of amphiphiles concentration (m). The accuracy of the γ measurements was within ±1.0 mN m−1. The experimental error in temperature was decreased to 0.2 K. Each and every data point attained by the tensiometric method is shown in Tables S1−S4 (Supporting Information). The relative uncertainties limits on the cmc were obtained as about 0.03. 2.2.2. Spectroscopic Measurements. The intrinsic fluorescence measurements for the pure drug, bile salts, and their mixed systems in aqueous solution were carried out using a F7500 fluorescence spectrophotometer from Hitachi, Japan,

in water.19 The S-enantiomer is supposed to be the additional pharmacologically active enantiomer. The sodium salt of ibuprofen (NaIbuF) possibly will cause several side effects, and their unwanted effect can be minimized if the salt is used with a proper drug carrier such as bile salts. Understanding the various physicochemical parameters of mixed monolayer and mixed micelles is when tuning drug delivery systems with essential characteristics. To the best of our knowledge, work on the physicochemical characterization of bile salts (NaC/NaDC) and the sodium salt of ibuprofen (NaIbuF) drug mixtures, both in absence and attendance of NaCl (100 mmol.kg−1), have not been done thoroughly; however, the literature regarding micellar, adsorption, and microstructural studies of bile salts with drugs is so far rare. Sodium deoxycholate (NaDC) and sodium cholate (NaC) are freely water-soluble compounds and have good suitability for pharmaceutical products (Scheme 2). Actually, NaDC is Scheme 2. Molecular Model of Bile Salts: (a) NaC and (b) NaDC

employed for the formulation of the antifungal agent such as amphotericin that is presently distributed as Fungizone.20 Owing to the amphiphilic nature of both components, the NaIbuF−NaC/NaDC mixed systems can be examined in light of various assumptions applied for surfactant−surfactant mixed systems. In the current study, we pay attention to the micellar as well as interfacial properties in addition to further parameters 3217



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Table 1. Source and Purity of the Compounds Employed in This Work chemical name

source

CAS number

ibuprofen sodium salt (NaIbuF) sodium cholate hydrate (NaC)b sodium deoxycholate NaCl pyrene (Py) Cetylpyridinium chloride monohydrate (CPC)b

Sigma (USA) Sigma (USA) Sigma (Germany) BDH (England) Sigma (USA) Merck (Germany)

31121-93-4 206986-87-0 302-95-4 7647-14-5 129-00-0 6004-24-6

purification methods vacuum vacuum vacuum vacuum vacuum vacuum

drying drying drying drying drying drying

mass fraction purity

analytic methods

≥0.98 0.99 ≥0.97 0.98 0.99

GCa NA NA NA NA NA

a Gas chromatography (provided by supplier). bAnhydrous salt obtained after drying the sodium cholate hydrate and cetylpyridinium chloride hydrate mentioned in the table. The water content in the hydrated salt determined using Karl Fischer analysis was found to be less than 100 ppm.

having a 10 mm path length quartz cuvette for aggregation number (Nagg) determination at 298.15 K. The emission spectra were taken between 450 to 600 nm at excitation wavelength of 335 nm by keeping the excitation and the emission slits width of 2.5 nm. For the evaluation of Nagg, the concentration of pure amphiphiles and their mixed systems were prepared above their respective cmc value. Py was employed as a probe whereas cetylpyridinium chloride (CPC) was employed as a quencher. The relative uncertainties on Nagg are expected to be 0.04. In the case of pure bile salts, the high concentration of Py was used in comparison to their mixture with NaIbuF (drug).

3. RESULTS AND DISCUSSION 3.1. cmc and cmcid in Absence/Presence of Salt. A representative illustration of the plot of surface tension (γ) versus logarithmic concentration (m) is shown in Figures 1−3

Figure 2. Variation of surface tension (γ) with concentration (m) for NaIbuF−NaDC mixtures in aqueous solution.

Figure 1. Variation of surface tension (γ) with concentration (m) for pure amphiphiles in the absence (filled symbols) and presence of 100 mmol·kg−1 NaCl solution (open symbols).

at temperature 298.15 K. By means of the rise in concentration, the γ value reduces approximately linearly and at assured concentrations, a significant change in slope occurs. The intersection point of the two straight lines (achieved from lower and higher concentration regions) was considered as a cmc. The cmc value of pure NaIbuF, bile salts, and, their mixtures in various ratios in the absence/attendance of salt were evaluated and given in Tables 2 and 3. The entire calculation for models applied in the current study was carried out by means of Microsoft Excel.

Figure 3. Variation of surface tension (γ) with concentration (m) for NaIbuF−NaDC mixtures in 100 mmol·kg−1 NaCl solution.

At 298.15 K the value of cmc of NaIbuF was attained to be 179.5 mmol·kg−1 in aqueous solution, and its value is close to a previously reported value.19 The value cmc of pure NaC and NaDC was obtained to be 9.0 mmol·kg−1 and 3.25 mmol·kg−1, respectively, which is also in good agreement with the earlier 3218



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Table 2. Various Physicochemical Parameters for NaIbuF−Bile Salts Mixed Systems in Aqueous Solution at Temperature T = 298.15 K and Pressure p = 0.1 MPaa α1 (bile salts)

cmc (mmol·kg−1)

cmcid (mmol·kg−1)

Xm 1

Xid1

fm 1

fm 2

0.8329 0.9301 0.9676 0.9876

0.9380 0.9101 0.9235 0.8941

0.5629 0.2590 0.1499 0.0566

0.9324 0.9735 0.9881 0.9954

0.8362 0.9585 0.9078 0.8852

0.1853 0.1669 0.0588 0.0223

ln(cmc1/cmc2)

NaIbuF + NaC 0 0.2 0.4 0.6 0.8 1

179.50 31.65 16.20 11.50 8.40 9.0

0.2 0.4 0.6 0.8 1

10.25 6.75 4.15 3.05 3.25

37.48 20.92 14.51 11.11

15.15 7.91 5.35 4.04

0.7498 0.7911 0.8301 0.8351 NaIbuF + NaDC 0.7543 0.8667 0.8440 0.8481

−2.99

−4.01

a Standard uncertainties (u) are u(T) = 0.20 K and u(p) = 5 kPa (level of confidence = 0.68). Relative standard uncertainties (ur) are ur(cmc/cmcid) id m m = 0.03, ur(Xm 1 /X1 ) = 0.03 and ur(f1 /f 2 ) = 0.04.

Table 3. Various Physicochemical Parameters for Mixed NaIbuF−Bile Salts Mixed Systems in the Presence of 100 mmol·kg−1 NaCl at Temperature T = 298.15 K and Pressure p = 0.1 MPaa α1 (bile salts)

cmc (mmol·kg−1)

cmcid (mmol·kg−1)

Xm 1

Xid1

fm 1

fm 2

0.8702 0.9470 0.9757 0.9908

0.9224 0.9229 0.9954 0.9842

0.4386 0.2229 0.3678 0.1079

0.9432 0.9779 0.9901 0.9962

0.9192 0.9620 0.9116 0.8954

0.2304 0.1505 0.0510 0.0199

ln(cmc1/cmc2)

NaIbuF + NaC 0 0.2 0.4 0.6 0.8 1

159.50 20.90 11.15 9.25 6.75 5.95

0.2 0.4 0.6 0.8 1

8.90 5.05 3.10 2.30 2.40

25.88 14.08 9.67 7.36

11.31 5.86 3.96 2.99

0.7616 0.8122 0.9370 0.9221 NaIbuF + NaDC 0.8068 0.8749 0.8501 0.8562

−3.29

−4.20

Standard uncertainties (u) are u(T) = 0.20 K, u(p) = 5 kPa, and u(NaCl) = 1 mmol·kg−1 (level of confidence = 0.68). Relative standard id m m uncertainties (ur) are ur(cmc/cmcid) = 0.03, ur(Xm 1 /X1 ) = 0.03 and ur( f1 /f 2 ) = 0.04.

a

reported value.28,29 The plot of surface tension (γ) versus logarithmic concentration (m) of pure amphiphiles used in the present study is shown in Figure 1. The presence of one more −OH groups in NaC in comparison to NaDC is the reason that NaC has a higher cmc value as well as more aqueous solubility. Drug NaIbuF and NaC/NaDC both have rigid hydrophobic structures, and as a result, they have the higher cmc values in comparison to the conventional surfactants. Even though the structure of NaC/NaDC is more complicated in comparison to that of NaIbuF, their cmc values are less than that of NaIbuF. This difference in cmc value is due to the manner of aggregation of both constituents. NaIbuF forms micelles in a predictable mode, whereas in the case of NaC/NaDC the aggregation occurs in a two-step course of action. Therefore, the drug begins aggregation at a higher concentration contrary to that of the NaC/NaDC (bile salts). We have also compared the earlier reported surface tension (γ) data of pure sodium cholate (NaC) and sodium deoxycholate (NaDC) with our obtained data graphically (Figure 4).30−32 The surface tension (γ) values of bile salts in the present study at all concentrations were found to be in agreement with the values of Mahajan and Mahajan32 within the limit of reported accuracy of surface tension value (Figure 4). In the current study, we performed

this experiment by a ring detachment method, whereas Mahajan and Mahajan measured the surface tension by Wilhelmy plate method.32 But in other mentioned references (Kumar and Chauhan, Chauhan et al.)30,31 surface tension data largely deviates from current reported values. The most probable reasons for the detected disagreement are (a) uncertainty in concentration of amphiphile, (b) effect of impurities, (c) and uncertainty of surface tension measurements. Another reason for the deviation of data is the method of measurement. Surface tension was measured by the drop weight method, and equilibration of molecules with the surface takes time. (Figure 4).30,31 Also the presently obtained cmc value of bile salts matches the cmc values achieved by Mahajan and Mahajan only, and the large difference found with the other above-mentioned references is also another reason for inconsistency of surface tension data.30−32 The cmc values of pure species (NaIbuF, NaC, and NaDC) together with their mixed systems decreases in attendance of the salt (Table 3). The amphiphiles form a charged monolayer at the interfacial surface, and upon the addition of salt in the solution the lowering of the thickness and potential of the electric double layer occurs at the interfacial surface.33 As a result, the electrostatic repulsion is weaker between the polar 3219



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groups as well as increases the electrostatic stabilization of the mixed micelle) and reduced hydrophilicity. These two joint consequences lead to a considerable reduction in the HLB (hydrophile−lipophile balance) value for the negatively charged amphiphiles mixtures. The sodium salt of the deoxycholic acid (NaDC) is additionally effective in decreasing the cmc of its mixed systems with the drug in comparison to NaC owing to the additional −OH group on the NaC that decreases their hydrophobicity. The hydrophobicity is inversely proportional to the number of −OH groups. NaDC connects strongly to the negatively charged drug ions and increases the hydrophobicity of the systems in comparison to NaC. Accordingly, micelles are produced at poorer concentration. 3.2. Interaction between Drug and Bile Salts in the Absence/Presence of Salt. The physicochemical interactions between drug molecules and bile salts systems are apparent themselves in terms of improved solubility of the drug, avoidance of drug precipitation if injected in the form of solution, and lessening of drug activity.37,38 The interactions between drug and bile salts can take place either at the interface or the inside of these higher structured associates. In vivo drug absorption in the occurrence of bile salts may be improved in view of consideration of the physicochemical interactions between drugs and bile salts. Therefore, a methodical study was proposed to describe the interactions of drugs with a variety of bile salts. The nature and potency of the interactions among the two amphiphiles in mixtures are exposed by evaluating the βm values, using the cmc’s obtained from surface tension (γ)− log(m) plots of the pure amphiphiles as well as their mixed systems, evaluated through the regular solution theory.39 Rubingh’s model is an optimization toward the cmc of the mixture from individual cmc’s.39 The interaction parameter (βm) is evaluated by the following equation:40

Figure 4. Variation of surface tension (γ) with concentration (m) for pure bile salts (filled symbols for NaC and open symbols for NaDC): ■,□, this work; ●,○, Kumar and Chauhan;30 ▲,△, Chauhan et al.;31 ▼,▽, Mahajan and Mahajan.32

head groups and makes the amphiphiles effectively more hydrophobic. This leads to a considerably lesser cmc value in contrast to that of the aqueous solution. The repulsion among amphiphiles head groups is the main cause for delaying aggregation.31 The enhanced hydrophobicity of amphiphiles by salt and the interaction between the molecules causing them to associate at inferior concentration means more micelles were produced by the addition of NaCl.34 In the mixtures of NaIbuF and bile salts, as the mole fraction (α1) of NaC/NaDC increases, a reduction in cmc takes place both in the absence and occurrence of salt suggesting good synergistic interaction among the components (Tables 2 and 3).2,30,35 Bearing in mind, that the cmc value of bile salts are lower as compared to the cmc of NaIbuF, the bile salts will form micelles instantaneously, beyond the mixed cmc, and the NaIbuF molecules intercalating into bile salts micelles means NaIbuF−bile salts mixed micelles are wealthy in bile salts components. Experimentally attained cmc values were also compared with theoretically computed cmc values achieved through the Clint equation:36 α1 α2 1 = + id cmc cmc (1) cmc 1 2

On an ideal state, micellar mole fraction of bile salts (Xid1 ) for the binary amphiphiles mixture can be estimated by the following relation41 α1 cmc 2 X1id = α1 cmc 2 + α2 cmc1 (4)

where α1 is the mole fraction of bile salts and α2 is mole fraction of drug. cmc1 and cmc2 are the values of NaC/NaDC and NaIbuF, respectively. Any deviation of experimentally estimated cmc from cmcid would be a statement for combined interactions between constituents. A positive divergence, that is, cmcid < cmc, indicates antagonism while negative variance, that is, cmcid > cmc, denotes synergism. In our case, a negative divergence for the experimental cmc from cmcid values signifies synergistic interactions between the components as shown in Tables 2 and 3. The considerable lessening of cmc is due to the increased hydrophobicity (intercalation of drug molecule into the bile salts micelles screens the repulsive interaction among head

Synergism in the mixed micelle formation occurs when the cmc of mixtures is below the pure amphiphiles cmc, and it is proven by following two circumstances:2 (i) βm should be negative and (ii) |βm| > |ln (cmc1/cmc2)|. A negative βm value indicates attractive interactions among the mixed components; a positive value means repulsive interactions, while values close to zero indicate ideal mixing. If there are more negative βm values, it means there is higher potency of the interaction between components. In the present study, the values of βm vary from −5 to −1 (Figure 5) demonstrating strong attractive interactions between the constituents in the mixed systems. The values of βm vary all over the different ratio of the component mixture and their magnitude rises with the rise of

βm =

ln(cmc α1/cmc1 X1m) (1 − X1m)2

(2)

where Xm 1 is the micellar mole fraction of anionic bile salts (component 1). Xm 1 can be achieved from the following equation:36 (X1m)2 ln[(α1cmc/X1mcmc1)] (1 − X1m)2 ln[(1 − α1)cmc/(1 − X1m)cmc 2]

3220

=1 (3)



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micelles would have almost a 95% contribution from bile salts. Xm 1 values are higher than α1 demonstrating that the bile salt replaces most of the NaIbuF (drug) component from the mixed micelles but it should be noted that the micellar mole fraction of drug (Xm 2 ) (contribution of drug in mixed micelles) is still more than the ideal micellar mole fraction of drug (Xid2 ) at all studied mole fractions (α1). The value of Xm 1 obtained is greater for NaIbuF + NaDC mixtures at all mole fraction in comparison to that for NaIbuF + NaC mixtures. This signifies that participation of sodium deoxycholate is high in mixed micelles in comparison to that of sodium cholate; therefore, the reduction in cmc of mixtures is also greater with the sodium deoxycholate than with the sodium cholate. For that reason, we can safely bring to a close that the sodium deoxycholate takes part effortlessly in the mixed micelle, more so than the sodium cholate; this supports the hydrophobic environment in the mixture resulting in the start of aggregation occurring at lesser concentration.49 id The Xm 1 and X1 values increase upon the addition of 100 −1 mmol·kg salt in the mixtures of NaIbuF and bile salts. The id rise in values of Xm 1 and X1 is due to the lessening of the repulsive interactions between the NaC/NaDC−NaC/NaDC head groups, NaIbuF−NaIbuF head groups, and NaIbuF−bile salts head groups. Consequently, the ionic strength of the aqueous solution increases and the charge on the head groups of components becomes neutralized. As a result, the interaction between the NaIbuF and bile salts is higher in attendance of NaCl and is also responsible for lessening the cmc and raising id the Xm 1 and X1 values. The activity coefficient illustrates the outcome as well as the involvement of individual components in mixtures; therefore, for this reason, it needs to be computed. Activity coefficients of m both components ( fm 1 (bile salts) and f 2 (NaIbuF)) in mixed amphiphiles systems can be calculated by means of the following equation:

Figure 5. Plot of variations of βm versus mole fraction of bile salts (α1) in NaIbuF−NaC/NaDC mixed systems at temperature T = 298.15 K in aqueous (filled symbols) and 100 mmol·kg−1 NaCl solutions (open symbols).

the mole fraction (α1) of bile salts with few exceptions. Herein, out of the above given two circumstances, only the first circumstance is satisfied. Therefore, it is suitable to employ the term “attractive interaction” more willingly than “synergism” within the whole range of amphiphile α1, in which a negative deviation from the cmcid is obtained. On the addition of salt in the solution, attractive interaction among the components was enhanced with few exceptions, as a result of the ionic strength of the solution increasing in the presence of salt, meaning βm becomes further negative (Figure 5).42,43 It is clear from Figure 5 that the values of βm for the different mixtures was found to be not constant with the variation in the mole fraction of the bile salts. The variation of βm values with composition is rather large, owing to the relative inaccuracy of the cmc determinations. The nonconstancy of βm with mixture composition shows the shortcomings of Rubingh’s approach for binary mixtures. For mixtures of ionic amphiphililes, it has been disputed that the interaction parameter must be a function of the composition because the electrostatic contribution to βm varies much with composition. Large differences in amphiphile headgroup size can also result in a composition-dependent interaction parameter.44 The nonconsideration of the effects such as counterion binding, chain length mismatch, ionic strength variation, etc. could be affecting the evaluation procedure and the results. However, the quality of our data does not warrant analysis based on a composition-dependent value of βm. According to regular solution theory (RST), for a particular system βm should remain independent of composition which is often not realized in practice. In this study, the parameter was found to be composition-dependent like earlier reports on anionic−nonionic mixtures.45−48 The values of micellar mole fractions (Xm 1 ) of bile salts (NaC/NaDC) are given in Tables 2 and 3. The values of Xm 1 as well as X1id are noticeably greater than the analogous stoichiometric mole fraction (α1) both in the absence and presence of salt (Tables 2 and 3). X1id shows continuous rise with increasing α1 of NaC/NaDC. The values of Xid1 are for all times greater than the Xm 1 values. These phenomena show that the mixed micelles enclose a lesser amount of NaC/NaDC in contrast to that in the ideal state; that is, in the ideal state

f1m = exp{β m(1 − X1m)2 }

(5)

f 2m = exp{β m(X1m)2 }

(6)

An activity coefficient is a factor employed in thermodynamics to report deviations from ideal behavior in a mixture of chemical substances. The activity coefficient is a measure of the excess chemical potential of a component from a mixture. Activity coefficient values for all mixed systems have been estimated and are shown in Tables 2 and 3. The values of m activity coefficients (fm 1 (bile salts) and f 2 (drug)) for mixed micelles components are obtained to be below 1, which suggests a nonideal behavior of the studied systems, signifying attractive interactions between components. The fm 1 values for the bile salts are noticeably higher (nearer to 1) which signifies that the bile salts in the mixture are close to the standard state. This type of obvious tendency was well accounted by Joshi et al.50 3.3. Effect of Salts on Interfacial Properties of NaIbuF−Bile Salts Mixture. It is recognized that amphiphiles in water have two affinities at a moment: first is to adsorb at the air−water interfaces and second is to associate to form micellar structures. The first phenomenon is only directly related to the equilibrium interface properties of amphiphiles.2 The examination of pure as well as mixed amphiphiles adsorption at air−water interfaces depends on the Gibbs adsorption equation.2,51,52 The surface excess concentration 3221



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Table 4. Surface Properties for Mixed NaIbuF−Bile Salts Mixed Systems in Aqueous Solutions at Temperature T = 298.15 K and Pressure p = 0.1 MPaa Xσ1

α1 (bile salts) 0 0.2 0.4 0.6 0.8 1 0.2 0.4 0.6 0.8 1

βσ

fσ1

f σ2

0.576 0.647 0.741 0.693

−3.14 −3.96 −3.17 −7.13

0.5685 0.6105 0.8081 0.5104

0.3520 0.1908 0.1751 0.0326

0.713 0.919 0.897 0.868

−3.72 −1.25 −2.69 −4.61

0.7368 0.9918 0.9720 0.9222

0.1510 0.3486 0.1151 0.0310

Γmax 107 (mol m−2)

Amin/ Aid (nm2)

NaIbuF + NaC 22.57 0.74 6.79 2.44/1.07 7.06 2.35/1.11 6.29 2.63/1.16 4.28 3.88/1.13 12.67 1.31 NaIbuF + NaDC 4.73 3.51/1.09 5.51 3.01/1.20 4.99 3.32/1.19 3.97 4.18/1.17 13.41 1.24

γcmc (mN m−1)

πcmc (mN m−1)

pC20

31.57 38.43 39.39 42.42 41.89 43.78

39.43 32.57 31.61 28.58 29.11 27.22

1.51 2.30 2.52 2.53 2.98 2.52

41.04 41.18 41.49 43.03 38.98

29.96 29.82 29.51 27.97 32.02

2.93 2.94 3.14 3.40 3.24

ln(conc1/conc2)

−2.17

−3.88

a Standard uncertainties (u) are u(T) = 0.20 K and u(p) = 5 kPa (level of confidence = 0.68). Relative standard uncertainties (ur) are ur(Xσ1) = 0.02, ur(βσ) = 0.03, ur( fσ1/f σ2) = 0.04, ur(Γmax) = 0.05, ur(Amin/Aid) = 0.05, ur(γcmc) = 0.02, ur(πcmc) = 0.02, and ur(pC20) = 0.03.

Table 5. Surface Properties for Mixed NaIbuF−Bile Salts Mixed Systems in the Presence of 100 mmol·kg−1 NaCl at Temperature T = 298.15 K and Pressure p = 0.1 MPaa Xσ1

α1 (bile salts) 0 0.2 0.4 0.6 0.8 1 0.2 0.4 0.6 0.8 1

βσ

fσ1

f σ2

0.572 0.613 0.691 0.717

−3.84 −6.02 −4.82 −6.18

0.4949 0.4061 0.6308 0.6105

0.2853 0.1040 0.1005 0.0416

0.751 0.811 0.906 0.795

−2.69 −3.18 −2.44 −6.57

0.8455 0.8930 0.9787 0.7584

0.2185 0.1233 0.1348 0.0157

Γmax 107 (mol m−2)

Amin/ Aid (nm2)

NaIbuF + NaC 22.75 0.73 6.69 2.48/0.91 5.31 3.13/0.92 6.11 2.72/0.94 3.92 4.22/0.95 15.96 1.04 NaIbuF + NaDC 6.20 2.68/1.49 5.40 3.07/1.55 5.14 3.23/1.65 4.46 3.73/1.54 9.52 1.74

γcmc (mN m−1)

πcmc (mN m−1)

pC20

29.67 38.68 39.42 40.15 43.02 43.72

41.33 32.32 31.58 30.85 27.98 27.28

1.61 2.50 2.90 2.82 3.06 2.63

39.51 41.01 40.94 41.84 42.04

31.49 29.99 30.06 29.16 28.96

2.95 3.16 3.29 3.58 3.44

ln(conc1/conc2)

−2.23

−3.84

Standard uncertainties (u) are u(T) = 0.20 K, u(p) = 5 kPa and u(NaCl) = 1 mmol·kg−1 (level of confidence = 0.68). Relative standard uncertainties (ur) are ur(Xσ1) = 0.02, ur(βσ) = 0.03, ur( fσ1/f σ2) = 0.04, ur(Γmax) = 0.05, ur(Amin/Aid) = 0.05, ur(γcmc) = 0.02, ur(πcmc) = 0.02, and ur(pC20) = 0.03. a

salts, and their mixed systems are shown in Tables 4 and 5 in both the absence and attendance of 100 mmol·kg−1 salt. The values of Γmax and Amin proposes that the amphiphiles molecules at the air−solution interface are closely or loosely packed. For pure bile salts, the value of Γmax and Amin are near to previous published values.32 The value of Γmax is less for bile salts as compared to that for NaIbuF; that is, Amin is greater in the case of bile salts in comparison to that of the NaIbuF. At ideal state minimum surface area per headgroup (Aid) can be calculated by means of eq 9.

(Γmax), meaning adsorption per unit of area, can be calculated by way of using surface tension data by following eq 7. Γmax = −

⎡ ∂γ ⎤ 1 ⎢ ⎥ 2.303nRT ⎣ ∂ log(m) ⎦

(mol m−2) (7)

In eq 7 n is the number of the chemical types in the solute. The value of n is 2 in the case of pure drug as well as for bile salts (NaC/NaDC). Therefore, n = 4 for NaIbuF and NaC/NaDC mixed systems. The slope of the tangent at the decided concentration of the surface tension vs log[m] plot was used to calculate Γmax. The Γmax was employed to compute the minimum area per headgroup (Amin) at the air−solution interface via the following equation:2 A min =

1018 NA Γmax

(nm 2)

Aid = X1σ A1 + (1 − X1σ )A 2

(9)

In eq 9 the Xσ1 is the mole fraction of NaC/NaDC in the mixed monolayer (which will be discussed in the later part of the paper). A1 and A2 are the area per headgroup of pure bile salts (NaC/NaDC) and drug (NaIbuF), respectively. In the case of binary mixtures of drug and bile salts, no specific trend was followed by Γmax or Amin in the absence as well as in attendance of NaCl. The experimental Amin values for mixtures are more than both Aid and Amin values of the pure drug and bile salts owing to the rigid as well as bulky hydrophobic volumes of both components that create a steric hindrance.

(8)

18

where the 10 factor is obtained from the conversion of the meter (m) to nanometer (nm) and NA is the Avogadro number. Γmax and Amin are e expressed in mol m−2 and nm2 units, respectively. The Γmax and Amin values for pure drug, bile 3222



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5. It is clearly visible that the γ value at cmc (γcmc) is the minimum for pure drug and maximum for pure bile salts, while for mixtures of both components the intermediate values are achieved in all systems in the absence/attendance of NaCl but near to pure bile salts. Thus, we can see that synergism in the effectiveness of γ reduction by NaIbuF−bile salt mixtures is fairly observed. The values of activity coefficient (fσ1 (NaC/NaDC) and f σ2 (NaIbuF)) in the mixed monolayer was estimated using the following relation:

Rosen suggests a model to estimate the mixed monolayer composition of both components as well as to know the effectiveness of interactions among the involved amphiphiles.2 In place of employing cmc values, here the concentration of pure (m1, m2), as well as mixture concentration (m) of the amphiphiles that required achieving a particular γ value, is used. The applicable equations are (X1σ )2 ln(mα1/m1X1σ ) (1 − X1σ )2 ln{m(1 − α1)/m2(1 − X1σ )}

=1 (10)

and βσ =

ln(mα1/m1X1σ ) (1 − X1σ )2

(11)

f1σ = exp{β σ (1 − X1σ )2 }

(12)

f 2σ = exp{β σ (X1σ )2 }

(13)

fσ1

f σ2

Values of and are given in Tables 4 and 5 in the absence/ attendance of NaCl. The activity coefficients of NaC/NaDC ( fσ1) are obtained to be higher than activity coefficients of NaIbuF ( f σ2), but less than 1, suggesting nonideal conduct and synergistic interaction among components. The efficiency of interfacial adsorption is helpful to calculate the necessary molar concentration of the components to build the highest adsorption. Highest adsorption of the species normally takes place as soon as the γ is decreased to 20 mN m−1. The molar concentration of the species at this instant is described its C20 value. The efficiency of adsorption (pC20) of species at the interfacial surface is evaluated by the following equation:2

where m1, m2, and m are the concentrations of bile salts, drug, and their mixtures solution, respectively. Xσ1 is the mole fraction of bile salts (component 1) at the interface, and βσ symbolizes the interaction parameter at the interfacial surface. The interaction parameter (βσ) at the air−water interface is zero for an ideal system. Positive βσ values indicate the repulsive interaction between components at the interface, while negative values show an attractive interaction for the binary mixture monolayer. The higher negative βσ values support strong attractive interaction. The values of Xσ1 and βσ are given in Tables 4 and 5. The obtained βσ values at the surface are found to be negative in all mixed systems signifying attractive interactions between the components at the interface, and drug + NaDC mixtures have more βσav (average value of βσ) values than drug + NaC mixtures. It recognized that NaDC is more hydrophobic in nature as compared to NaC in the absence/attendance of NaCl, meaning that the interaction between the drug−NaDC mixture at the monolayer is greater in comparison to that of the drug− NaC mixture. The average values of Xσ1 are less than average values of Xm 1 denoting that the interface contains less NaC/ NaDC than the mixed micelles. Due to less hydrophobicity of the drug species (rigid structure) favor the surface of the solution mixture, as a result, less NaC/NaDC is there in comparison to the drug.. The values of Xσ1 were also found to be greater in the case of the drug + NaDC mixture than in the NaC + NaIbuF mixture in all cases in the absence/attendance of NaCl, again proving that NaDC is more hydrophobic than NaC. In the current study, the βσav (average) values were found to be greater than βm av (average) in all cases in the absence/ presence of NaCl except for the NaDC + NaIbuF mixture in the absence of salt. The more negative values of βσav than those of βm av are because of greater difficulty of integrating the large hydrophobic parts inside of the cylindrical/spherical micelle in comparison to the planar interfacial surface.53 The βm values, shown in Figure 5, are negative having average (βm av) values of −2.51 and −1.86 for drug + NaC mixed systems in the absence and attendance of NaCl, respectively. For the NaIbuF + NaDC mixtures the βm av value is −3.65 and −3.54 in the absence/ attendance of NaCl, respectively, suggesting attractive interactions between the components. In the case of drug + NaDC mixtures, the βm av value is higher than that of the drug + NaC mixtures which again proved that NaDC is more hydrophobic than NaC. From the surface tension isotherms presented in Figures 1 to 3 the values of γ at the cmc (γcmc), have been found. The γcmc values for all investigated systems are presented in Tables 4 and

pC20 = −log C20

(14)

The greater is the value of pC20, the lesser concentration is required to reduce the value of γ by 20 mN m−1, signifying that the amphiphile solution has high surface activity, meaning better adsorption as well as more efficient reduction of the surface tension. The mixtures of drug and sodium salt of bile acid have higher pC20 values than the pure drug but lower values than pure bile salts except at the highest mole fraction of bile salts (Tables 4 and 5). The pC20 value is higher for NaC/ NaDC in comparison to that for NaIbuF, signifying the NaC/ NaDC has more surface activity as compared to the drug. This result is also sustained by the low cmc value of bile salts. The pC20 value rises with greater α1 of NaC/NaDC, and at higher α1 of bile salts the value is more than the pure bile salts. In the case of the drug + NaDC mixed system having more pC20 value in comparison to the drug + NaC mixed system, this shows an enhanced adsorption efficiency at the interfacial surface of the drug−NaDC mixtures in the absence/attendance of NaCl. In the attendance of 100 mmol·kg−1 NaCl the pC20 value increases in the case of pure species and their mixtures showing that surface activity increases in the attendance of NaCl. 3.4. Thermodynamic Properties. Micellization in aqueous/nonaqueous solution is a thermodynamically approved as well as a spontaneous process followed by a considerable reduction in free energy. According to the phase separation model, the standard Gibbs free energy (ΔG0m) of aggregation54−56 can be evaluated by eq 15. ΔGm◦ = RT ln Xcmc

(15)

In the above equation, the new term Xcmc is the cmc of an amphiphile revealed in mole fraction units. There are different probable interactions among the components of the solutions. Therefore, an entire account of the thermodynamic associated parameters is not achievable as a variety of factors, for example, 3223



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The standard free energy of interfacial adsorption (ΔG°ads) at the interfacial surface is achieved by following equation,58,59

charges, polarity, hydrophobicity, etc., are associated with them, and owing to these factors the uncertainties in values are large. The values of ΔG0m obtained to be negative for all pure and mixed systems in the absence/presence of salt (Table 6). This

◦ ΔGads = ΔGm◦ −

Table 6. Thermodynamic Parameters for Mixed NaIbuF− Bile Salts Systems in Aqueous and Nonaqueous Solutions at Temperature T = 298.15 K and Pressure p = 0.1 MPaa α1 (bile salts)

ΔGom (kJ mol−1)

ΔGoads (kJ mol−1)

Gmin (kJ mol−1)

ΔGm ex (kJ mol−1)

ΔGσex (kJ mol−1)

NaIbuF + NaC 0 −14.51 0.2 −19.54 0.4 −21.09 0.6 −21.55 0.8 −22.33 1 −22.65 NaIbuF + NaDC 0.2 −21.65 0.4 −23.05 0.6 −24.26 0.8 −25.01 1 −24.89

−31.68 −66.44 −64.92 −66.41 −89.79 −43.09

−0.47 −0.88 −0.96 −1.40

−1.90 −2.24 −1.51 −3.76

−1.36 −0.68 −1.29 −1.68

−1.88 −0.23 −0.61 −1.31

−0.64 −0.86 −0.17 −0.47

−2.33 −3.57 −2.55 −3.10

−0.87 −0.67 −1.30 −2.21

−1.25 −1.21 −0.51 −2.66

13.99 56.55 55.77 67.37 97.85 34.54

−84.56 86.64 −76.48 74.77 −82.57 82.99 −94.76 108.39 −48.02 29.07 100 mmol·kg−1 NaCl solution −32.68 −67.84 −80.56 −72.06 −93.69 −39.74

13.04 57.81 74.23 65.73 109.71 27.39

−72.44 −78.57 −82.80 −90.44 −55.33

63.73 75.91 79.73 93.89 44.18

(16)

where πcmc is the surface pressure at cmc and is equal to (γ0 − γcmc) and Γmax is the maximum surface excess of the amphiphile. γ0 is the γ of pure solvent and γcmc is that of the solution at cmc. From Table 6, we can be found that the ΔG°ads values are found to be negative in the absence/attendance of NaCl, demonstrating adsorption phenomena are spontaneous owing to the hydrophobicity of species, which escorts them toward the interfacial surface. The values of ΔG°ads are larger in magnitude than that of ΔGm ° in the absence/attendance of NaCl signifying that, as soon as a micelle is formed, additional work must be performed to transport the amphiphiles in its monomeric form at the interface to the micellar phase in solution. It means micellization is the secondary process. We can also see from Table 6 that ΔGads ° values for mixtures are greater in magnitude as compared to the pure species, so that the adsorption process turns out to be more facile for the mixed monolayer systems which means an increase in the aggregation phenomena at the interfacial surface in mixtures (Table 6). Sugihara and co-workers60 recommended an equation to estimate Gmin (minimum free energy of a surface at maximum adsorption achieved at cmc) as

aqueous solution NaIbuF + NaC 0 −14.21 0.2 −18.51 0.4 −20.17 0.6 −21.01 0.8 −21.79 1 −21.62 NaIbuF + NaDC 0.2 −21.29 0.4 −22.33 0.6 −23.54 0.8 −24.30 1 −24.15

πcmc Γmax

Gmin = γcmcA min NA

(17)

The lesser is the value of Gmin, the more stable is the surface produced or the higher is the surface activity attained. The low values of Gmin of the pure drug (NaIbuF), the sodium salt of bile acid (NaC/NaDC), and their mixed systems signify that thermodynamically stable surfaces are produced; therefore, the NaIbuF and NaC/NaDC interactions are favorable both in the absence/attendance of salt (Table 6). The excess Gibbs energy of the mixed monolayer (ΔGσex), as well as that of mixed micelle formation (ΔGm ex) can be evaluated using eqs 18 and 19:61−65

a

Standard uncertainties (u) are u(T) = 0.20 K, u(p) = 5 kPa and u(NaCl) = 1 mmol·kg−1 (level of confidence = 0.68). Relative standard uncertainties (ur) are ur(ΔGom) = 0.03, ur(ΔGoads) = 0.04, ur(Gmin) = σ 0.04 and ur(ΔGm ex/ΔGex) = 0.05.

ΔGexσ = RT[X1σ ln f1σ + (1 − X1σ ) ln f 2σ ]

(18)

ΔGexm = RT[X1m ln f1m + (1 − X1m) ln f 2m ]

(19)

The evaluated values of ΔGσex and ΔGm ex were negative suggesting the mixed monolayer and mixed micelle formation are more stable in comparison to monolayer and micelles of a single species (Table 6). It can be also seen from the table that the values of ΔGσex are greater than ΔGm ex at almost all α1 of NaC/NaDC showing that the stability of the mixed micelles formation is less as compared to mixed monolayer formation. The magnitude of ΔGσex and ΔGm ex values were found to be more in attendance of NaCl with few exceptions signifying that the stability of solution mixtures is further enhanced in the presence of salt. NaCl reduces the electrostatic repulsion among the head groups of species of mixed micelles by increasing the ionic strength of the solution.66 In the present study, it can be seen that the interaction parameters are not constant with respect to mole fraction (α1) of components which means that the excess free energies for the mixed micellization involved will not be symmetrical or the molecular interactions deviate from the symmetrical solution showing the shortcomings of the Rubingh approach.67

reveals that the NaIbuF and NaC/NaDC mixed system has considerable spontaneity throughout the micelle formation, as well, their negative value increases by way of the rise in mole fraction of NaC/NaDC (Table 6). The value of ΔGom for pure NaIbuF as well as bile salts is obtained to be in very good agreement with the previously accounted value.32,57 The value of ΔG0m obtained for bile salts is more than the ΔG0m value of the drug. This happens because of the small hydrophobicity of the drug which moderatley hinders the aggregation phenomena. The Gibbs energy of micellization (ΔGom) is at all times additionally negative in the occurrence of NaCl in comparison to aqueous solutions, representing easy facilitation of the micellization process because the driving force for aggregation was greatly improved with NaCl (Table 6). The ΔG0m values for the drug + NaDC mixture are greater in magnitude in comparison to the drug + NaC mixture in the absence/ attendance of NaCl suggesting that in the NaIbuF−NaDC mixed systems the micellization processes are more spontaneous. 3224



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3.5. Micropolarity. The interactions between NaIbuF (drug) and NaC/NaDC (bile salt) have further been examined by utilizing the steady-state fluorescence spectroscopic technique. Fluorescence spectrum of pyrene (Py) is a fairly dependable tool to reveal the polarity of the microenvironment, as the ratio of the first vibrational peak (I1) positioned at 373 nm and third vibrational peak (I3) located at 384 nm is extremely sensitive to that polarity,68 and the ratio of first and third vibronic peak is called micropolarity (I1/I3). The amphiphile starts to aggregate, whereas Py species will be solubilized inside the hydrophobic province of micelles that are a source of a rapid variance of the I1/I3 ratio; therefore, the Py spectra was utilized to examine the interaction between drug and bile salts micelles. The I1/I3 value of various mixture solutions has been estimated by combining the stock solution of both species in different ratios at more than their respective cmc value. Every spectrum has 1 to 5 vibronic peaks commencing with lower to higher wavelengths (Figure 6).

Table 7. Aggregation Number (Nagg), Micropolarity (I1/I3), Stern−Volmer Constant (Ksv), Calculated Sielectric Constant (Dexp) and Ideal Dielectric Constant (Dideal) for NaIbuF−Bile Salts Mixed Systems in Aqueous Solutions at Temperature T = 298.15 K and Pressure p = 0.1 MPaa α1 (bile salts)

Nagg

0.0 0.2 0.4 0.6 0.8 1.0

44 16 22 28 36 9

0.2 0.4 0.6 0.8 1.0

20 29 34 42 12

I1/I3

Ksv (×10−4)

NaIbuF + NaC 1.26 0.94 1.58 7.47 1.19 5.24 1.16 1.75 1.08 1.62 1.28 1.05 NaIbuF + NaDC 1.33 7.07 1.32 7.08 1.29 0.96 1.27 0.85 1.34 0.68

Dexp

Dideal

20.50 44.43 14.74 12.41 6.60 22.07

21.76 21.82 21.89 21.88

25.63 25.03 22.79 21.22 27.23

27.05 28.16 27.86 27.97

a

Standard uncertainties (u) are u(T) = 0.20 K and u(p) = 5 kPa (level of confidence = 0.68). Relative standard uncertainties (ur) are ur(Nagg) = 0.04, ur(I1/I3) = 0.03, ur(Ksv) = 0.03, and u(Dexp/Dideal) = 0.04.

equation reveals the accessibility of the Py to the CPC (quencher) and can be evaluated using eq 20:70 I0 = 1 + KSV[Q ] I1 (20) Q is the concentration of quencher (CPC). The values of Ksv are estimated by the slope of above equation and shown in Table 7. The solubilization of Py in the micellar solution generally limits to the palisade layer.71 Therefore, if an efficient nonpolar hydrophobic environment is obtainable in the micelles of mixed systems, it would make possible the solubilization of Py and CPC together as well as carry them in a very near locality for valuable quenching. The higher is solubilization of the Py and CPC in the micelles, the greater will be the value of Ksv (Table 7). Ksv values for the mixtures of NaIbuF and NaC/NaDC are higher in comparison to that of the pure amphiphiles (NaIbuF, NaC/ NaDC). This denotes that CPC (quencher) and Py are present in a higher hydrophobic environment. However, Ksv values demonstrate a decline by increasing the α1 of bile salts. This signifies that the CPC is incapable of moving toward an excited state Py, which is implanted in a strong hydrophobic environment. This possibly is because of the bulky structure of bile salts which restricts its interactions with Py. 3.6. Aggregation Number (Nagg). The aggregation number (Nagg) describes the entire number of species monomers forming the micelles by individual or mixtures of amphiphiles. The Py amount was invariably reserved in solution, and the concentration of CPC (quencher) was changed from the lower to the higher value. CPC does not influence the absorption as well as the fluorescence spectra of Py. The fluorescence intensity of the Py probe was reduced in the occurrence of the CPC (quencher). The Nagg value of the mixed systems of drug and bile salts was evaluated via the static fluorescence quenching technique by means of eq 21:72

Figure 6. Representative fluorescence (emission) spectra of 10−6 M pyrene in NaC (0.2) + NaIbuF (0.8) mixture at different quencher concentrations (maximum intensity indicates no quencher and minimum intensity indicates maximum amount of quencher).

The I1 (first) and I3 (third) are the vibronic peaks, which reduce by the increase in quencher concentration. A small value of I1/I3 indicates a nonpolar environment, while a high value advocates a polar environment. Figure 6 shows the fluorescence spectra of 10−6 M Py of the (0.2 NaC + 0.8 NaIbuF) mixed system at various quencher (CPC) concentrations. All values of micropolarity (I1/I3) for the pure species and their mixtures are shown in Table 7. The high values of I1/I3 for the pure species (NaIbuF, NaC, NaDC) in addition to their mixed systems signify the microenvironment of the micelles to be nearly polar like that of hydrocarbon solvents.69 Therefore, it may be believed that Py is dissolved in the palisaded layer of aggregates. From the table, we observed that the I1/I3 value in micellar region decreases with rising mole fraction of NaC/NaDC ascribed to the enhanced hydrophobic interactions of the mixed micelles in all the solvent media, so the environment sensed by Py is less polar in accordance with the decreased cmc values. The Stern−Volmer relationship was employed to acquire the Ksv (equilibrium constant) value in support of the interaction involving the CPC as a quencher and the Py as a probe. This

⎛I ⎞ Nagg[Q] ln⎜ 0 ⎟ = ⎝ I1 ⎠ ST − cmc 3225

(21) DOI: 10.1021/acs.jced.7b00298 J. Chem. Eng. Data 2017, 62, 3216−3228


Article

where, I0 and I1 are the fluorescence intensities in the absence and attendance of CPC, correspondingly. [Q] is the concentration of CPC; ST shows the total concentration of amphiphile. The values of Nagg for the different solutions were evaluated from the slopes (= Nagg/{[S] − cmc}) of the linear plots between ln (I0/I1) versus [Q]. The Nagg values of pure NaIbuF, bile salts, and their mixtures are shown in Table 7. The Nagg of the pure drug and bile salts in aqueous solution are obtained to be in good conformity with reported values.27,73 We can clearly see from Table 7 that the Nagg values for mixture solutions in aqueous solution increase with an increase in the mole fraction of NaC/NaDC but are less than the Nagg of pure drug. This specifies an encouraging mixed interaction in all mixed systems leading to the formation of packed mixed micelle structures. The apparent dielectric constant (Dexp) of the studied solutions can be evaluated by means of using eq 22:74−77 I1 = 1.00461 + 0.01253Dexp I3

NaDC is due to the electrostatic and hydrophobic interactions being effective at the same time.

■

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jced.7b00298. Concentration (m) versus surface tension (γ) data of pure drug, bile salts, and their mixed systems in the absence and presence of salt (PDF)

■

∑ DiXi

AUTHOR INFORMATION

Corresponding Author

*Tel.: +966 563671946. E-mail: [email protected], [email protected]. ORCID

Malik Abdul Rub: 0000-0002-4798-5308 Abdullah M. Asiri: 0000-0001-7905-3209

(22)

Funding

This project was funded by the Center of Excellence for Advanced Materials Research (CEAMR), King Abdulaziz University, Jeddah, under Grant No. CEAMR-SG-4−438.

In the current study, Dexp values for micelles of the pure drug, bile salts, and their mixtures were evaluated from I1/I3 data. The Dexp value was obtained to be greater for pure NaC/NaDC micelles in comparison to that for pure NaIbuF (Table 7). Dexp values decrease with rise in the α1 of bile salts. The values of Dexp fall in between 20 to 45 in the case of pure and mixed species. Dexp values obtained in the present study are closer to methanol/ethanol Dexp values, once more proving that the environment of Py is polar.78 The values of ideal dielectric constant (Dideal) for the mixtures can be evaluated by the following equation:74 Dideal =

ASSOCIATED CONTENT

Notes

The authors declare no competing financial interest.

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REFERENCES

(1) Phenomena in Mixed Surfactant Systems; ACS symposium series, Vol. 311; Scamehorn, J. F., Ed.; American Chemical Society: Washington, DC, 1986. (2) Rosen, M. J. Surfactants and Interfacial Phenomena, 3rd ed.; John Wiley & Sons: New York, 2004. (3) Suradkar, Y. R.; Bhagwat, S. S. CMC Determination of an odd carbon chain surfactant (C13E20) mixed with other surfactants using a spectrophotometric technique. J. Chem. Eng. Data 2006, 51, 2026− 2031. (4) Rub, M. A.; Asiri, A. M.; Naqvi, A. Z.; Khan, A.; Khan, A. A. P.; Kabir-ud-Din. Kabir-ud-Din. Interaction of amphiphilic drug imipramine hydrochloride with gemini surfactants at different temperatures. J. Mol. Liq. 2014, 194, 234−240. (5) Rub, M. A.; Azum, N.; Asiri, A. M. Self-association behavior of an amphiphilic drug nortriptyline hydrochloride under the influence of inorganic salts. Russ. J. Phys. Chem. B 2016, 10, 1007−1013. (6) Kumar, D.; Rub, M. A. Aggregation behavior of amphiphilic drug promazine hydrochloride and sodium dodecylbenzenesulfonate mixtures under the influence of NaCl/urea at various concentration and temperatures. J. Phys. Org. Chem. 2016, 29, 394−405. (7) Wang, J.; Zhang, H. Effects of carbon numbers and concentration of alkanol cosurfactants on the CMC and thermodynamic properties of span80 in N,N-dimethylformamide solvent by microcalorimetry. J. Chem. Eng. Data 2015, 60, 2694−2700. (8) Kumar, D.; Rub, M. A. Effect of anionic surfactant and temperature on micellization behavior of promethazine hydrochloride drug in absence and presence of urea. J. Mol. Liq. 2017, 238, 389−396. (9) Coello, A.; Meijide, F.; Nunez, E. R.; Tato, J. V. Aggregation behavior of bile salts in aqueous solution. J. Pharm. Sci. 1996, 85, 9− 15. (10) The Bile Salts; Small, D., M. Nair, P. P., Kritchevsky, D., Eds.; Plenum Press: New York, 1971; Vol. 1, p 249. (11) Mysels, K. J. Surface Tension studies of bile salt association. Hepatology 1984, 4, 80S−84S. (12) Ć irin, D. M.; Poša, M. M.; Krstonošić, V. S. Interactions between selected bile salts and Triton X-100 or sodium lauryl ether sulfate. Chem. Cent. J. 2011, 5, 89−97. (13) Natalini, B.; Sardella, R.; Gioiello, A.; Ianni, F.; di Michele, A.; Marinozzi, M. Determination of bile salt critical micellization

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It is obvious that values of Dexp for mixed micelles are quite different in comparison to the values of Dideal (Table 7). This occurs because of some attractive interactions inside the mixed micelle of both components used in the present study in aqueous solution.

4. CONCLUSIONS The present study deals with the understanding of interactions between the drug (NaIbuF)−bile salt (NaC/NaDC) through measurements by tensiometry and fluorometry methods. It can be seen from the results, that the cmc values of the drug−NaC/ NaDC mixed systems are much less in comparison to the pure drug cmc value, owing to which the side effect of the drug is decreased and their performance is improved. Because of the presence of salt, cmc values of pure species as well as that of their mixed system decreased. Mixed micelles of NaIbuF− NaC/NaDC are also characterized with negative interaction parameter values; the real binary mixture micelles are thermodynamically more stable in comparison to the ideal mixed micelle. The negative ΔGom and ΔGoads values confirm that micelle formation and adsorption at the interfacial surface of pure NaIbuF, NaC/NaDC in addition to their mixed systems is energetically favorable. The values of Nagg for the mixture of NaIbuF−bile salt increases with increasing of α1 of NaC/ NaDC. Ksv values for mixtures are higher in comparison to that of the pure species owing to the greater hydrophobicity created by the involved species in the mixed system. Our results reflect that the strong interaction between the NaIbuF and NaC/ 3226



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