Enhanced micellization of Gemini surfactants using diphenhydramine hydrochloride as an organic counterion

Journal of Molecular Liquids 300 (2020) 112288

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

Enhanced micellization of Gemini surfactants using diphenhydramine hydrochloride as an organic counterion Anirudh Srivastava a, Hiromasa Uchiyama a, Hideki Imano a, Hiroshi Satone b, Kenji Iimura b, Kazunori Kadota a, Yuichi Tozuka a,⁎ a b

Department of Formulation Design and Pharmaceutical Technology, Osaka University of Pharmaceutical Sciences, 4–20–1 Nasahara, Takatsuki, Osaka 569–1094, Japan Department of Chemical Engineering, Graduate School of Engineering, University of Hyogo, 2167, Shosha, Himeji, Hyogo 671-2280, Japan

a r t i c l e

i n f o

Article history: Received 10 September 2019 Received in revised form 5 December 2019 Accepted 8 December 2019 Available online 10 December 2019 Keywords: Micellization Counterion binding constant Binding constant Mean occupancy ion per micelle Aggregation number

a b s t r a c t Micellization of the Gemini surfactant sodium dilauramidoglutamide lysine (SDGL) in the presence of an antihistamine drug, diphenhydramine hydrochloride (DPC) was investigated. The anionic surfactant sodium dodecyl sulfate (SDS) was used for comparison. DPC significantly decreased the critical micelle concentration (cmc) of both SDGL and SDS in aqueous media and increasing the DPC concentration decreased the pyrene excimer/ monomer polarity ratio in SDGL micelles but increased it in SDS micelles, suggesting that SDGL and SDS micelles have different shapes. The counterion binding and binding constant values reveal that SDGL micelles interact more strongly with DPC than SDS micelles. Thus, DPC, as an organic counterion, can enhance surfactant micellization. The evaluation of the solubility of a poorly water-soluble drug (clotrimazole) in SDGL and SDS micelles containing DPC revealed that the drug was more soluble in SDS micelles than SDGL micelles, indicating that the cmc and the shape and size of micelles are essential factors for controlling drug solubilization. © 2019 Elsevier B.V. All rights reserved.

1. Introduction Ionic surfactants with hydrophilic heads and hydrocarbon tails are widely used in industrial and academic research. Micelle formation characteristics are essential properties of ionic surfactants and amphiphilic drugs [1,2]. The properties of ionic amphiphilic compounds are affected by the electrolyte, solvent, and temperature [2–7]. Also, ion adsorption affects counterion binding and the critical micelle concentration (cmc), aggregation number (na), and phase/shape transitions at the micellar interface. Corrin and Harkins explained the interaction between charged counterions and monomers of ionic surfactants using a model for counterion binding to micelles (the so-called CH approach) [2,3]. It has been reported that large organic compounds can be used as organic counterions to enhance the interfacial and micellization properties of ionic surfactants [7–13]. Ionic surfactant micellization is also affected by the hydrophobic interactions between the micellar core and the hydrophobic moiety of organic counterions. Generally, large organic counterions can penetrate the micellar core, thus favoring micellar growth [14–17]. Mukherjee et al. reported that tetramethyl, tetraethyl and tetra-npropylammonium could act as counterions and enhance the

⁎ Corresponding author. E-mail address: [email protected] (Y. Tozuka).

https://doi.org/10.1016/j.molliq.2019.112288 0167-7322/© 2019 Elsevier B.V. All rights reserved.

micellization of sodium dodecyl sulfate (SDS) [12]. Anacker et al. investigated the formation of decyl trimethylammonium micelles using nalkyl carboxylate ions with carbon chain lengths from one to six [13]. The increasing size of the alkyl group resulted in a decrease in the cmc of the ionic surfactant in both studies. Akram et al. studied the micellization behavior of cationic Gemini surfactants in the presence of inorganic and organic salts (potassium chloride, potassium nitrate, potassium thiocyanate, sodium benzoate, and sodium salicylate) [11]. The authors examined the influence of ions on the responsive distribution of forces controlling the micelle structure and solution properties of charged amphiphilic molecules. Sugahara et al. also demonstrated that inorganic and organic counterions significantly influenced oleic acid-based Gemini surfactants [18]. They found that the use of smaller inorganic counterions (Li+, Na+, K+, and Cs+) reduces the cmc and the repulsive electrostatic interaction between the head-to-head groups of Gemini surfactants. Further, the hydrophobicity of organic counterions (monoethanolamine and diethanolamine) affects the micellization properties of Gemini surfactants. Numerous studies have reported the effects of organic counterions on cationic Gemini surfactants [19–22]. However, there are few reports of the effects of adding organic counterions on the cmc and shape of anionic Gemini surfactant micelles [18,23]. In the present study, we used a Gemini surfactant, sodium dilauramidoglutamide lysine (SDGL). SDGL (Fig. S1) has a tripeptide structure composed of two hydrophilic headgroups (glutamic acid) with negative charges and one spacer (lysine) and two hydrophobic

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chains (lauroyl groups with twelve‑carbon chains) in each molecule. SDGL is a biodegradable surfactant that shows an excellent interfacial effect between hydrophilic and lipophilic phases. Sekiguchi and Moriyama et al. reported the cmc of SDGL as 1.2 mmol L−1 in a buffered system [24–26]. However, the physicochemical properties of SDGL in distilled water have not been reported to date. In this study, SDS is used for comparison with SDGL. SDS has a sulfate headgroup with a negative charge and one hydrophobic chain with a carbon length of twelve. DPC has a positively charged headgroup and two phenyl moieties as the hydrophobic part (Fig. S1). DPC is an antihistaminic drug that is used to treat allergies [27], and a surface-active amphiphilic drug with a cmc of 94.4 mmolL−1 in aqueous media [29]. The use of salt formulations of pharmaceutical drugs containing organic counterions in micellar systems has not been reported thus far. Herein, the interaction of DPC as an organic counterion with ionic surfactants was investigated. The CH approach has not been used to assess drug binding in ionic micelles. Therefore, using the CH approach, the objectives of this study were to evaluate the drug–micelle interactions in aqueous solution. The counterion binding (B), binding constant (Kb), and mean occupancy of DPC per surfactant micelle (i0) were calculated from surface tension and UV spectroscopy measurements [9,28,29]. These data were used to explain the binding properties of DPC in the micellar environment. The ratio of the first (373 nm) and third (384 nm) vibronic peak intensities (I1/I3) was calculated from the pyrene emission spectrum, thus providing a measure of the apparent environmental polarity. The fluorescence intensity ratio of the excimer and monomer (IE/IM) was determined by measuring the monomer (393 nm) and excimer (440 nm) fluorescence intensities, which provided the rate of diffusion of pyrene and the distribution of the probe in the micelles. Dynamic light scattering (DLS) experiments were used to measure the size of the surfactant micelles in the absence and presence of DPC. We used clotrimazole (CLO) as a model drug in this study. The permeability of CLO to skin and mucosa is low because of its poor aqueous solubility (0.49 μg/mL), making it a challenging target for the study and development of drug delivery systems. Finally, the solubilities of CLO in SDGL and SDS micelles containing DPC were compared. 2. Experimental section 2.1. Materials SDGL (Pellicer L–30, ≥99%) was provided from Asahi Kasei Chemicals Co., Ltd. (Japan). DCP (≥99%) was purchased from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan). CLO (≥98%) and cetylpyridinium chloride monohydrate (CPC) (≥99%) were purchased from Wako Pure Chemical Industries Ltd. (Osaka, Japan). SDS (≥99%) was purchased from Nacalai Tesque, Inc., Kyoto, Japan. Throughout the study, Millipore water was used. The structures of SDGL, SDS, DPC, and CLO are shown in Fig. S1. 2.2. Experimental techniques 2.2.1. Surface tension measurements An online tensiometer (SITA Science Line t60; SITA Messtechnik GmbH, Dresden, Germany), which can collect the entire dynamic range of surface tension values by measuring the bubble pressure, was used to measure the surface tension of each solution prepared at 25 °C. A long bubble life of 1000 ms was used to calculate the changes in surface tension under semi-static conditions. The tensiometer was calibrated prior to the experiment and a sample vessel was prepared with Millipore water for calibration. The clean capillary was placed in a capillary holder in the tensiometer and the command “clean” was initiated at least thrice. After cleaning, the tensiometer was turned on and the “clean” command was initiated twice to begin auto-calibration. The temperature was controlled by the built-in thermometer and maintained at 25 ± 0.2 °C. The calibration was completed by immersing

the capillary in the water without immersion of the capillary holder, exhibiting a surface tension value of 72.0 mN m−1 (±5% mN m−1). 2.2.2. UV–visible measurements A Hitachi U–2900 spectrophotometer and quartz cuvettes with path lengths of 1 cm were used to determine the Kb for DPC in SDGL/SDS solution. For this study, the concentration of DPC was 0.1 mmol L−1, and the concentration of surfactants was varied. Similarly, the Kb for CLO in SDGL/SDS was determined in different concentrations of DPC solution. 2.2.3. Steady-state fluorescence measurements The pyrene probe method was used to determine na values for SDGL and SDS. The concentration of pyrene in all mixtures was 0.00375 mmol L−1. A spectrofluorophotometer (RF–5300 PC, Shimadzu, Japan) was used to measure the excitation pyrene wavelength at 336 nm, and the spectra were obtained from 350 to 400 nm. I1 and I3 refer to the intensity of the fluorescence emission spectra of pyrene at 373 and 384 nm, respectively. A similar experiment was used to determine the IE and IM intensity ratio from the pyrene fluorescence emission spectrum (0.00375 mmol L−1) at 393 and 440 nm. 2.2.4. Dynamic light scattering A Nanotrac ultrafine particle analyzer (UPA) (UT151, Microtrac BEL Co., Ltd., Japan) DLS instrument at 635 nm (20 mW He-Ne laser) with a scattering angle of 90° was used to determine the micelle size of the SDGL and SDS at 15.0 mmol L−1 in the absence and presence of DPC. All samples were filtered through 0.22-μm membrane filters before measurement. 2.2.5. Encapsulation efficiency (EE, %) A total surfactant concentration of 200.0 mmol L−1 was used for the surfactant solutions, and a CLO concentration of 13.0 mmol L−1 was added to these solutions. In a shaking water bath ((37 ± 0.2) °C at 100 rpm; ML-10 TAITEC Corporation, Japan), sample tubes were placed for 24 h. The prepared samples then centrifuged at 4000 rpm for 5 min (Kubota Corporation, Japan), and the supernatants were carefully removed. The drug concentration was measured using highperformance liquid chromatography (HPLC) immediately after filtering through 0.22-μm filters. HPLC analyses were conducted using a reversed-phase HPLC system from Waters Alliance (e2695 and 2489; Waters, Milford, USA) with a COSMOSIL 5C18-MS-II column (5 μm, 150/4.6 mm; Nacalai Tesque, Inc.). Samples were eluted with a mobile phase consisting of acetonitrile and ultrapure water (50:50, v/v) using a 1.0 mL/min isocratic flow rate. The injection volume was 10 μL, and the column temperature was kept at (40 ± 0.2) °C. The UV–Vis absorption intensity at 254 nm was determined, and the CLO content was calculated from a calibration curve. The EE (%) values of CLO in SDGL/SDS with different DPC concentrations were calculated using Eq. (1). EEð%Þ ¼

ðC observed Þ  100% ðC initial Þ

ð1Þ

Here, Cobserved is the experimental concentration from HPLC, and Cinitial is the total amount of drug. 3. Results and discussion 3.1. Surface tension and cmc of SDGL and SDS in the absence and presence of DPC The surface tensions of SDGL and SDS were measured in the absence and the presence of DPC (Fig. 1). Reductions in the surface tensions of SDGL and SDS were observed as the DPC concentration increased. The surface activities of SDGL and SDS were determined from the surfactant concentration (pC20) in the absence and presence of DPC, as obtained

A. Srivastava et al. / Journal of Molecular Liquids 300 (2020) 112288

3

Fig. 1. Representative surface tension plots of aqueous (A) sodium dilauramidoglutamide lysine (SDGL) and (B) sodium dodecyl sulfate (SDS) solutions in the presence of diphenhydramine hydrochloride (DPC) at 25 °C ± 0.2 °C. Relative standard uncertainties, ur for surface tension = ±5%.

from surface tension experiments. The adsorption efficiency at the air/ water interface is the negative logarithm of the surfactant molecule concentration required in the bulk phase to decrease the surface tension of the solvent by 20 mNm−1 (pC20 = –logC20). The concentration of SDGL (pC20) continued to decrease until the DPC concentration reached 60.0 mmol L−1. The concentration of SDS (pC20) continued to decrease until 10.0 mmol L−1 of DPC was added. The concentration of SDS (pC20) then increased as the DPC concentration increased. These results suggested that DPC interacts synergistically with SDGL and SDS micelles. The cmc values of SDGL and SDS [5,30] in aqueous solution were 14.0 and 8.0 mmol L−1, respectively. Comparing the cmc values of SDGL and SDS in the presence of DPC, the cmc of SDGL was found to be lower than that of SDS, suggesting a strong interaction between SDGL and DPC (Fig. 2(A)). The aggregation properties of DPC were reported and the cmc of DPC was determined to be 94.4 mM in aqueous media [29]. The hydrophobic interactions between DPC and SDGL were low when the concentration of DPC was lower than that of SDS (0.0–1.0 mmol L−1 of DPC). This was likely because the SDGL cmc was higher than that of SDS. SDGL is double chained, which imparts good solubilization properties for DPC [31]. When the DPC concentration increased from 3.0 to 130.0 mmol L−1, excess DPC was solubilized in an

SDGL micelle that changed the internal atmosphere of the micelle, causing it to behave in a similar manner as a high concentration DPC-rich micelle [29,31]. This resulted in a lower surface tension and decreased the cmc values. SDS is a single hydrophobic chained surfactant with a higher cmc in comparison with that of SDGL in the presence of DPC [32]. 3.2. Binding of DPC to the micelles The counterion binding constant of the ionic surfactant was measured using Eq. (2) [3,4]. ln c0 ¼ A1 −β ln ðc0 þ cd Þ

ð2Þ

The terms c0 and cd represent the cmc and the concentration of the added drug, respectively, and A1 is a constant associated with the standard micellization free energy. In Eq. (2), the term (c0 + cd) is the total free counterion concentration at the cmc if the added drug has the same counterion as the ionic surfactant. However, the addition of DPC adds a different counterion to the system, so Eq. (2) is not applicable. The values calculated using Eq. (2) describing SDGL and SDS micelle counterion binding behavior and the deviations from linearity of the plots of lnc0 versus ln(c0 + cd) are shown in Fig. 2(B).

Fig. 2. (A) Variation of the cmc of sodium dilauramidoglutamide lysine (SDGL) (square) and SDS (circle) with the diphenhydramine hydrochloride (DPC) concentration at 25 °C ± 0.2 °C. Plots of the (B) Corrin-Harkins (CH) and (C) modified CH equations for the aqueous solutions of SDGL-DPC and SDS-DPC. Relative standard uncertainties, ur for cmc = ±5%.

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Mukhim et al. [7] modified Eq. (2) using the Gibbs–Duhem approach because of the inapplicability of Eq. (2) for mixed counterion types. SDGL and SDS are dissociated in aqueous media as Na+ (sodium ion), DGL− (dilauramidoglutamide lysine ion), and DS− (dodecyl sulfate ion). Similarly, DPC also dissociates into DP+ (diphenhydramine ion) and Cl− (chloride ion) in aqueous media. The formation of one mole of micelles (SDGL/SDS) was considered as n (na) moles of DGL− and DS− monomers bound with m1 moles of Na+ and m2 moles of DP+ cations. In the presence of mixed counterions [4–10], the micellization equilibrium can be represented as. nDGL− =DS− þ m1 Naþ þ m2 DPþ ⇌DGLm or DSm

ð3Þ

Here, DGLm/DSm refers to the SDGL/SDS micelle with bound counterions. Using the mass-action model and the thermodynamic relationship between the equilibrium constant and the free energy change, we applied the following relationship [7]: −




ln ½DGL  ¼

−

ln ½DS  ¼




 ln ½DGLm  þ na

 ln ½DSm  þ na

!

     ΔG0mic m1 m2 − ln Naþ − ln DP þ ; na RT na na

!

     ΔG0mic m1 m2 − ln Naþ − ln DP þ ; na RT na na

ð4bÞ Here, ΔG°m is the standard free-energy of micellization per mole of ionic surfactant monomer. Equilibrium between the drug and surfactant in the micellar phase was reached when the concentrations (c) of SDGL and SDS were equal to or greater than the cmc (c0 ). When c N c 0 , [Na + ] = c 0 + (c − c 0 ) (1 − β1 ) and [DP+] = cd − (c − c0)β2, where β1 = m1/na is the binding constant for Na+ in SDGL or SDS, β2 = m2/na is the binding constant for the DP+ counterion, and β = β1 + β2 is the total binding constant. Because the concentrations of SDGL/SDS were slightly above c 0 , Eq. (4) was simplified using the method of Ismail et al., as shown in Eq. (5) [4–10]. ln c0 ¼ A2 −B ln cd

ð5Þ

Here, A2 = ΔG°mic/[(1 + β1)RT] and B = β2(1 + β1). We plotted lnc0 against lncd, and the linearity of these plots (Fig. 2(C)) confirmed the suitability of Eq. (5) for modelling the presence of different counterions. Also, this result indicated that the DP+ counterion could act as an organic counterion for the SDGL and SDS micelles. The total binding constant (β) can be calculated as β = B + β1(1 + B) [4–10]. Therefore, β and β2 should be higher than B such that B b β b 1 and B b β2 b β [4–10]. The least-squares fitted values, B = 0.594 and 0.148 and A2 = −9.19 and − 6.33 were determined from Fig. 2(C) for DP+–DGL¯ and DP+–DS¯ mixed systems, respectively. These values suggest that DP+ binds more strongly with SDGL micelles than with SDS micelles. Because β2 = B(1 + β) / (1 + B), both β2 and β1 can be determined if β is known [4–10]. The maximum possible value for β is 1.0. For DP+– DGL− and DP+– DS−, β1 could not exceed 0.255 and 0.798, respectively. The value of β for SDS in aqueous media has been reported to be 0.7 [30]. Interestingly, the B value of SDS micelles containing DP+ was lower than that in SDS alone. We found the β value (β = S2/S1, where S1 is the slope in the region below the cmc and S2 is the slope above the cmc in the conductance plot (Fig. S9)) [33] for SDGL to be 0.573 from the conductivity data. The numbers of DP+ bound per micelle (m2 = β/na) were, thus, almost equal to 7.72 and 10.18 for SDGL and SDS, respectively, considering that the na values were 13.07 and 68.8, respectively. Consequently, DP+ was mostly bound to the SDGL micelles, resulting in the significant suppression or reduction of Na+ binding to the SDGL micelles. The number of DP+ cations bound per SDS micelle

was higher in comparison with that of the SDGL micelles because the electrostatic interaction between DP+ and SDS induced the formation of a mixed micelle [29].

3.3. Spectrophotometric approach UV spectrophotometry was used to evaluate the binding constants of DPC in SDGL and SDS surfactant micelles. The procedure was carried out by the successive addition of the SDGL and SDS stock solutions and absorption measurements at wavelengths of (260 ± 2) nm (Fig. S2). The experimental data were used to obtain Kb values using Eq. (6) [9,29,34,35].

N m 1 1 1 1 ¼ þ A−Aw Am −Aw K b ðAm −Aw Þ ðc−c0 Þ

ð6Þ

Here, A is the measured absorbance, and Aw is the absorbance of DP+ in the absence of SDGL or SDS micelles. Am is the absorbance of the DP+ bound to SDGL or SDS micelles. Further, c0 is the cmc of SDGL or SDS, and c is the total concentration of SDGL or SDS. Nm is the number of moles of micelle per mole of bound DP+ molecules. In Fig. 3(A1 & 2), the data are plotted as 1 / (A − Aw) vs 1 / (c − c0), and their linearity indicates that Eq. (6) is appropriate if the Nm values are 1.0. The value of Nm was, thus, considered almost equal to 1.0, and the absorbance data indicate a 1:1–type binding between DP+ and the micelles [9]. We have reported drug–surfactant interactions in our previous work and found that Nm = 1.0 is the best value for Eq. (6) [9,29,34,35]. Similarly, Caetano et al. [36] measured absorbance data for chlorpromazine and trifluoperazine in aqueous cetyltrimethylammonium chloride solution and obtained a comparable relationship to Eq. (6). Moreover, the Nm values for chlorpromazine were found to be between 0.90, and 1.14 and those of trifluoperazine ranged from 1.00 to 1.12. The value of Kb was determined using the slope and intercept values from Fig. 3(A1 & 2). As shown in Table 2, the K b values of DPC were higher in SDGL than in SDS. The SDGL Gemini surfactant has a double carbon chain, whereas SDS has a single carbon chain, as shown in Fig. S1. Hydrophobic and electrostatic interactions were likely responsible for the higher or lower K b values. The hydrophobic interactions occurred via interaction between the hydrophobic chains of SDGL and hydrophobic moiety of DP+ in the micellar medium. Moreover, electrostatic interactions occurred via interactions between the head groups of DGL − and DP+ counterions in the SDGL micellar medium. DPC is a large organic counterion (DP + ) that can penetrate toward the micellar core [14–17] and change the micellar medium (as discussed further in Section 3.1), resulting in higher Kb values. Similar observations for the interaction of anionic surfactants with chlorpromazine were reported by Caetano et al. [37]. Herein, it can be concluded that the protonated portion of DPC is located close to the polar head region of the micelle, while its hydrophobic component is situated closer to the micelle inner core. Electrostatic interactions decreased the maximum area per head group, inducing micellar growth, which may be responsible for the lower Kb values.

3.4. CH approach combined with spectrophotometric approaches In our previous work, we were combined the CH and spectrophotometric approaches using Db = (c − c0)m2/na [9]. Here, Db represented the binding of DP+ to SDGL or SDS micelles. At the limiting condition, the CH approach can only be applied when c is almost equal to the cmc. Thus, the binding constant was determined using Eq. (7) from

A. Srivastava et al. / Journal of Molecular Liquids 300 (2020) 112288

5

Fig. 3. Plots (A-1) Sodium dilauramidoglutamide lysine (SDGL) - Diphenhydramine hydrochloride (DPC) and (A-2) Sodium dodecyl sulfate (SDS)-DPC according to Eq. (6) showing the variation of 1 / (A − Aw) with 1 / (c − c0)Nm. The solid red line showed the linear fitting used to determine the Kb from the intercept and slope ratio. Plots (B-1) SDGL-DPC and (B-2) SDSDPC showed the variation of micelle mean occupancy (estimated from the absorbance data) with micelle concentration. The solid red line showed the exponential fitting used to determine the i0 from the empirical equation (as shown in Table S1). The DPC concentration was given in the inset. Relative standard uncertainties were ur = ±5%. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

the absorbance, Nm ≈ 1 [9].

Km b

½D  m2 ¼  b ¼ cd D f ½M 

3.5. Interfacial properties of drug–surfactant binding

ð7Þ

Here, [Df] is the concentration of DP+ in the bulk solution (free DP+ in water only) and M is the concentration of SDGL or SDS micelles. Eq. (7) has also been reported by Pineiro et al. [28], i.e. i0 = cdKb, where i0 is defined as the mean initial occupancy of the micelle at very low surfactant concentrations [9,28] when both the concentration of bound DP+ (Db) and the concentration of the micelle [M] tend to zero. The micelle can have a high mean occupancy near the cmc depending on the total concentration of the drug and the Km b. Thus, the equation from Pineiro et al. [28] was used to calculate the mean number of drug molecules per micelle (mean occupancy), i, which depends on the concentrations of both the bound drug and micelles, i.e., i = [Db]/[M] (Fig. 3(B1 & 2)). The Db values were estimated by first determining the concentration of free DP+ (Df) from the obtained absorbance data. Fig. 3(B1 & 2) depict that i decays with increasing micelle concentration, which can be fitted using an exponential equation for i vs. [M] to yield i0 = 11.45 and 16.99 for DP+ in SDGL and SDS micelles, respectively. Therefore, m2 = 7.76 and 9.63 (m2 = β2 × na) for DP+ in the SDGL and SDS micelles, respectively. The m2 values were slightly different from those achieved from the CH approach because of the different experimental techniques (surface tension and UV absorbance). Therefore, this study supports our earlier report [9] that the UV absorbance method can be used to determine the counterion binding constants of surfactants containing drugs or the number of bound drug ions per micelle at the Nm cmc (m2 or i0). Interestingly, at the cmc, Km (from Eq. (6)) b = K bn [9] and, for DPC in SDGL and SDS micelles, the K m b values were found to be 3.26 and 3.76, respectively. Possibly, the cmc values of SDGL were higher (14.0 mmol L−1), thus limiting the DPC binding −1 (i.e., Km ) b ) to SDGL at cmc. In contrast, the cmc of SDS (8.0 mmol L was lower than that of SDGL, which could be the reason for the slightly higher DPC binding (i.e., Km b ) at the cmc.

In the presence of DP+, the added DGL− and DS− monomers could form ion pairs with DP+. The adsorption of these DP+-DGL− and DP − ion-pairs might be treated as like that of non-ionic surfactant +-DS [6,7,9,10,30]. Therefore, the surface excess (Γcmc) of the SDGL and SDS solutions in the presence of DPC could be calculated using Eq. (8).

Γcmc

0 1

 1 B 1 C dγ ¼− @ A c0 RT dln c 1þ c0 þ cd

ð8Þ

In Eq. (8), R and T represent the gas constant and absolute temperature, respectively. The value of the slope dγ/dlnc at the cmc was determined from the surface tension data (Fig. 1). The determined Γcmc value (2.98 × 10−6 mol m−2) for SDS is similar to values found in the literature [5,6]. The Γcmc value of SDGL was calculated as 0.7 × 10−6 mol m−2. In aqueous solution, the value of Γcmc increased when the DPC concentration was increased to 30.0 mmol L−1 and became almost constant at DPC concentrations above 30.0 mmol L−1 in both SDGL and SDS solutions. The addition of DPC might have caused a decrease in the surface area per adsorbed surfactant molecule, Amin (Amin = 1020)/ (NAΓcmc), where NA is Avogadro's constant, and Amin is in units of angstroms squared (Å2). For the SDGL–DPC system, the trend in Amin with DPC concentration was opposite to that of Γcmc (Table 1). The surface area covered by the SDGL molecule decreased with an increase in added DPC, followed by an increase in Γcmc. For the SDS–DPC system, the Γcmc initially decreased when DPC was added because of the decrease in the slope dγ/dlnc. From the decrease in dγ/dlnc,it was assumed that the extent of surface tension reduction caused by the addition of SDS was limited in the presence of DPC, as shown in Table 1. The Γcmc increased until 60.0 mmol L−1 of DPC was added, reaching a plateau value when N60.0 mmol L−1 of DPC was added, indicating that monolayer saturation occurred at DPC concentrations of N60.0 mmol L−1 by the formation of ion pairs between DP+ and DS−. Interestingly, in the presence of DPC, the Γcmc value of SDS was higher than that of SDGL. In the next

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A. Srivastava et al. / Journal of Molecular Liquids 300 (2020) 112288

Table 1 The values of different parameters for SDGL and SDS in the absence and presence of DPC. DPC (mM)

πcmc

pC20

cmc (mM)

Γmax (mol m−2)

ΔG°mic (kJ mol−1)

ΔG°ads (kJ mol−1)

Amin (Å2)

na

23.6

1.91

14.00

0.74

−20.53

−52.42

2.24

13.07

26.4

2.58

8.560

0.86

−21.74

−52.44

1.94

59.75

26.2

2.71

6.670

0.99

−22.36

−48.83

1.67

72.12

25.4

2.74

3.580

1.01

−23.90

−49.05

1.65

81.05

27.9

2.90

2.170

1.28

−25.14

−46.94

1.19

98.43

28.6

3.00

1.890

1.50

−25.49

−44.55

1.10

82.37

28.5

3.07

1.250

1.67

−26.51

−43.58

0.99

74.55

28.2

3.38

0.605

2.68

−28.31

−38.83

0.62

70.30

22.5

3.39

0.452

2.62

−29.03

−37.62

0.63

68.78

17.4

–

0.439

2.50

−29.11

−36.07

0.66

64.19

14.4

–

0.430

2.45

−29.16

−35.04

0.68

55.07

37.0

2.39

8.000

2.98

−21.91

−34.33

0.56

68.79

39.6

3.20

5.400

0.92

−22.88

−65.93

1.79

84.33

36.6

3.28

5.090

0.96

−23.03

−61.16

1.73

81.05

36.1

3.31

4.340

1.09

−23.43

−56.55

1.52

76.76

36.1

3.34

3.930

1.26

−23.67

−52.32

1.28

75.50

36.8

3.35

3.600

1.33

−23.89

−51.56

1.04

58.47

34.4

3.00

3.050

2.21

−24.30

−39.87

0.75

48.75

28.0

2.89

2.720

2.88

−24.59

−34.31

0.57

43.73

22.4

2.67

2.500

3.54

−24.80

−31.12

0.47

34.45

13.6

2.48

2.450

3.35

−24.85

−28.91

0.49

29.63

10.9

2.05

2.320

−24.98

−28.12

0.48

30.42

SDGL 0.000 0.500 1.000 3.000 5.000 10.00 15.00 30.00 60.00 90.00 130.0 SDS 0.000 0.500 1.000 3.000 5.000 10.00 15.00 30.00 60.00 90.00 130.0 mM = mmol L−1, Relative standard uncertainties (u) were u(T) = ± 0.2 °C. Relative standard uncertainties, = ±5%, ur for πcmc = 5%, ur for pC20 = ±5%, ur for cmc = ±5%, ur for Γcmc, ur for Amin = ±5%, ur for ΔG°mic and ur for ΔG°ads = 5% and ur for (na) = 5%.

Section 3.6, we reported that the free energy of micellization of SDGL was more negative than that of SDS. This could be because of the higher counterion binding (B) and the binding constant of DPC to the micelles. SDGL has a double chain, and DP+ interacts with two hydrophobic chains. As a result, the number of DP+ molecules bound to SDGL micelle increased near the air–solution interface, resulting in decreased repulsive interaction between the negatively charged head groups of SDGL. The repulsive interaction decreased, stretching the head groups at the interface and decreasing the Amin value or increasing the Γcmc value of SDGL. On the other hand, SDS has a single hydrophobic chain, and the interaction between DP+ and SDS was lower compared to SDGL. As Table 2 The values of binding constant Kb (c N c0) and Km b at cmc and mean occupancy of ion per micelle (i0) for DPC in the presence of SDGL and SDS by liner and exponential fitted values. Surfactant SDGL SDS

DPC (mM)

Intercept

0.1 0.1

1.8006 2.1890

Slope 0.0128 0.0274

Nm 1 1

σa

Log Kb

Log Km b

i0

0.975 0.981

2.14 1.90

3.26 3.76

11.45 16.99

σb 0.995 0.997

mM = mmol L−1, Relative standard uncertainties, ur for (LogKb) = ±5%, ur for (Log Km b ) = ±5%, and ur for (i0) = ±5%.

discussed above, the mean occupancy of DP+ ions were higher in SDS micelle compared to SDGL micelle. The interior of the SDS micelle strongly interacted with DP+ hydrophobic part, which helps to form the close micellar packing. As a result, the DP+ hydrophobic part reduced the repulsive interaction between DS− monomers, which helped to push more DS− monomers to the air–water interface, resulting in higher Γcmc values. 3.6. Thermodynamic properties In terms of the interaction parameter, the synergistic effect could be quantified by its relation with the free energy of micellization, ΔG°mic (Table 1) [29,33–35] as follows: ° ΔGmic ¼ RT ln cmc

ð9Þ

As presented in Table 1, the ΔG°mic values of SDGL and SDS increase with increasing DPC concentration, suggesting synergistic interactions between SDGL or SDS and DPC. The ΔG°mic value for pure SDGL was less negative than that of SDS, suggesting that the micellization process is more spontaneous.

A. Srivastava et al. / Journal of Molecular Liquids 300 (2020) 112288

7

Table 3 The values of binding constant Kb (c N c0) and Km b at cmc and mean occupancy of ion per micelle (i0) for CLO in the presence of SDGL and SDS with varying DPC by liner and exponential fitted values. Surfactant

DPC (mM)

CLO (mM)

Intercept

Slope

Nm

σa

Log Kb

Log Km b

i0

σb

SDGL

0.00 0.50 1.00 3.00 5.00 0.00 0.50 1.00 3.00 5.00

0.05

4.59 6.11 4.41 1.31 0.51 12.9 6.20 1.82 1.52 1.60

0.034 0.049 0.076 0.136 0.156 0.305 0.381 0.460 0.503 0.540

1 1 1 1 1 1 1 1 1 1

0.990 0.996 0.996 0.975 0.983 0.973 0.986 0.986 0.970 0.987

2.13 2.09 1.76 0.98 0.51 1.62 1.21 0.59 0.48 0.47

3.24 3.87 3.62 2.89 2.51 3.46 3.13 2.50 2.36 2.34

73.32 88.37 98.36 113.7 119.6 293.1 347.1 422.2 431.1 440.9

0.999 0.996 0.995 0.992 0.996 0.996 0.998 0.995 0.991 0.987

SDS

0.05

σa and σb is the correlation coefficient. mM = mmol L−1. Relative standard uncertainties, ur for (LogKb) = ±5%, ur for (Log Km b ) = ±5%, and ur for (i0) = ±5%.

Spontaneity indicated that the synergistic interaction for DPC-SDS was higher in comparison with that of DPC-SDGL in the presence of 0.0–0.5 mmol L−1 DPC (Table 1). This was because the cmc value of SDGL was higher than that of SDS (DPC 0.0–0.5 mmol L−1). The DPC concentration was increased from 1.0 to 130.0 mmol L−1, resulting in more dramatic increases in ΔG°mic values for SDGL in comparison with SDS. The more negative values of ΔG°mic suggested that SDGL micellization was more favorable in comparison with that of SDS in the presence of DPC (N1.0 mmol L−1). This result is possible because SDGL consists of two hydrophobic chains, favoring micellization to a larger degree than the single-chain SDS [31,32,39]. Rosen and Aronson [40] used the following equation to describe the relationship between ΔG°mic and ΔG°ads (standard Gibbs energy of adsorption): πcmc ° ° ΔGads ¼ ΔGmic − ; Γmax

ð10Þ

where πcmc is the surface pressure (πcmc = γ0 − γcmc), while γ0 and γcmc are the surface tensions of the aqueous or DPC solution and the solution at the cmc, respectively. Eq. (10) is significant because it describes the transfer of a surfactant molecule from a monolayer to the micelle at zero-surface pressure [41,42]. The values of ΔG°ads in the absence or presence of DPC were more negative than ΔG°mic for SDGL and SDS, Table 4 The values of encapsulation efficiency (EE%) for CLO in the presence of SDGL and SDS with varying DPC in the aqueous medium. DPC (mM)

SDGL

SDS

19.61

47.51

21.32

48.76

22.53

50.07

22.99

63.55

25.45

69.54

28.39

71.12

31.32

73.06

36.78

76.59

42.87

77.09

50.80

79.02

54.70

79.26

0.000 0.500 1.000 3.000 5.000 10.00 15.00 30.00 60.00 90.00 130.0 mM = mmol L−1, Relative standard uncertainties, ur for (EE%) = ±5%,

indicating that SDGL and SDS adsorptions at the air/water interface were more favorable than micellization (Table 1) [31,32,39,41,42]. 3.7. Turbidity and micelle size Analysis of the solution turbidity was conducted to detect colloidal micelles in solutions with a constant concentration of DPC and different concentrations of surfactants. A UV–Vis spectrophotometer was used to measure the turbidity of sample solutions at a wavelength of (260 ± 2) nm at a temperature of (25 ± 0.2) °C. We investigated the phase behavior of solutions with increasing SDGL (Fig. S3(A)) and SDS (Fig. S3 (B1–8)) concentrations in the absence and presence of different concentrations of DPC. We studied the prepared SDGL and SDS samples in three respective regions for the phase behavior (clear to turbid) of the solution: below the cmc (0.4 mmol L−1), at the cmc (Table 1), and above the cmc at 15.0 mmol L−1. Both SDGL alone and SDGL with 0.5 to 30.0 mmol L−1 of DPC showed transmission (T, %) values of over 95% for all three regions at the same wavelength, as shown in (Fig. S3(A)). Anisotropic solution assumed that small (≈3.5 nm) spherical micelles were formed [43], as shown in Fig. 4(A). The SDGL micelle sizes (Fig. S4) were 3.0–5.2, 2.4–5.5, and 3.3–8.0 nm in the region below the cmc, at the cmc, and above the cmc, respectively, with different concentrations of DPC. Interestingly, the size of the SDGL micelles did not much change after the addition of DPC into the solution from 0.5 to 60.0 mmol L−1. The size of the SDGL micelles increased slightly with increase in DPC from 90.0 and 130.0 mmol L−1 (Fig. 4(A)). This is because the Kb of DPC was increased in the SDGL solution. The SDS solution alone showed UV–vis transmission N98% at the same wavelength in aqueous solution (Fig. S3(B1)). In aqueous solution, the measured SDS micelle size was about 4.2 nm, which is consistent with the reported values [38]. The transmittance in the presence of DPC from 0.5 to 30.0 mmol L−1 changed to 3.0%, 0.05%, 2.2%, 13.6%, 15.5%, 13.6%, and 19.3% in the region below the cmc (SDS = 0.4 mmol L−1), respectively. When a small amount of SDS was present in DPC solutions, larger aggregate was formed compared to SDS alone micelle, as shown in Fig. S5. The solution in the region below the cmc had fewer monomers of SDS, and more DPC monomers could form a DPC rich aggregate in the solution [38,44]. The transmittance decreased sharply at the cmc (Table 1), as shown in Fig. S3(B–8), indicating that, in the presence of DPC at 0.5 to 30.0 mmol L−1, the SDS solution changed from clear to a homogeneous turbid solution The turbidity increased at the cmc, and the SDS micelle size was also increased in the presence of DPC at the cmc (Fig. S5). As stated above, the Log Km b values were higher than Log Kb, which could be responsible for the increased electrostatic interaction between SDS and DPC at cmc [29,38,44,45]. Above the cmc (SDS = 15.0 mmol L−1), the transmittance decreased for DPC concentrations of 0.5 to 30.0 mmol L−1, as shown in Fig. S3

8

A. Srivastava et al. / Journal of Molecular Liquids 300 (2020) 112288

Fig. 4. Hydrodynamic sizes of the (A) sodium dilauramidoglutamide lysine (SDGL)- diphenhydramine hydrochloride (DPC) and (B) sodium dodecyl sulfate (SDS) - DPC solutions at fixed SDGL/SDS concentrations (mmol L−1) and varying DPC concentrations (mmol L−1) at 25 ± 0.2 °C. Relative standard uncertainties, ur for the hydrodynamic size (nm) = ±5%.

(B2–8). Above the cmc, the prepared solution cleared, and the micelle size was significantly smaller in DPC solutions, as shown in Fig. S5 and Fig. 4(B), respectively. The 30.0 mmol L−1 DPC solution had a 32.3% lower transmission because of the opacity and large micelle size of 1446 nm. The turbidity test could not be performed at N30 mmolL−1 of DPC due to scattering in the transmittance data. We performed DLS studies at DPC concentrations of 60.0, 90.0, and 130.0 mmol L−1 below the cmc, at the cmc, and above the cmc, as shown in Fig. S5. SDS micelle sizes of 750, 500, and 50 nm were found at DPC concentrations of 60.0, 90.0, and 130.0 mmol L−1 below the cmc (0.4 mmol L−1), 1200, 850, and 350 nm at the cmc, and 1487, 1570, and 2063 nm above the cmc (SDS = 15.0 mmol L−1, Fig. 4(B)). Two possible explanations for the large micelle sizes exist: (i) the small micelles aggregated again to form larger aggregates [33] and (ii) some free DPC molecules were weakly bound to the Stern layer below the SDS head group, enhancing the hydrophobic interaction between the free DPC and SDS and inducing large catanionic aggregate formation [29,45,46]. 3.8. Steady-state fluorescence quenching study Using Eq. (11), the na values of SDGL and SDS as a function of DPC concentration in aqueous media were determined from pyrene fluorescence quenching data.   ln I0 =Iq ¼ ½Q na ðc−cmcÞ

ð11Þ

Here, I0 and Iq represent the pyrene fluorescence emission intensities in the absence and presence of the quencher, CPC, respectively, and [Q] is the quencher concentration. The value of c - cmc was kept constant at 15.0 mmol L−1. The plots of ln(I0/Iq) vs [Q] are shown in Fig. S6. The value of na for SDS in aqueous solution value was 68.8, which is consistent with the reported values [5,46]. The na value for SDGL in aqueous solution was 13.07 and has not been reported previously. The turbidity and micelle size data indicate that, for aqueous SDGL in the presence of DPC, similar types of micelle (spherical) were formed, as shown in Table 1. Initially, the na value of SDGL increased until the DPC concentration reached 5.0 mmol L−1 because of the binding of DP+ to the SDGL micelles, which reduced the repulsion between the DGL− head groups. The na values of SDGL decreased when the DPC concentration increased (from 10 to 130.0 mmol L−1) because of the penetration of the micelle core with excess DP+ cations (Table 1). Moreover, the na values of SDS decreased with increasing DPC concentrations (from 0.5 to 130.0 mmol L−1), as shown in Table 1. The solution behavior of the SDS–DPC systems reveals the different micelle types or mixed micelle, as discussed in Section 3.7. As reported previously, DPC is a surface-active amphiphilic drug with a typical micelle size of 1.1 nm [29]. Thus, excess DPC monomers may contribute to the

development of DPC-rich mixed micelles, resulting in reduced na values with increasing DPC concentration. The SDS na values predicted that the micelle shape could be changed by adjusting the DPC concentration. Previously reported studies of SDS in NaCl solution have shown that the micelles change from a spherical to rod-like shape [46]. The changes in micelle shape induced by salt addition have also been reported previously using the pyrene I1/I3 and IE/ IM ratios [6,10,46–48]. In this study, the pyrene vibrionic intensity ratios of the first (I1 = 373 nm) and third peak (I3 = 384 nm) and the IE/IM ratio with a monomer (IM = 393 nm) and excimer (IE = 440 nm) peak were determined. As shown in Fig. 5(A & B), the pyrene I1/I3 and IE/IM ratios of the SDGL micelles decreased with increasing DPC concentration. Fig. 5(A, inset) shows that the I1/I3 ratio decreased and the ionic strength increased. This could lead to a decrease in the apparent polarity in the SDGL–pyrene micelles, possibly because of the reduction in micellar water content in the presence of DPC. On the other hand, the IE/IM ratio in the SDGL micelles sharply reduced with increase in DPC concentration from 0.5 to 15.0 mmol L−1 (Fig. 5(B)) but was almost constant at DPC concentrations N30.0 mmol L−1. Further, excimer formation was reduced with increasing concentration of DPC, which suggests that pyrene was dispersed in the SDGL micelles. This is possible for the small spherical shape and size of the formed micelles. The pyrene polarity results are given in Fig. 5(A) show that the I1/I3 ratio in SDS micelles containing DPC decreased sharply until the DPC concentration reached 30.0 mmol L−1 but was almost constant after the DPC concentration reached 60.0 mmol L−1. The single chained SDS favored the tight packing of DS− monomers, decreasing the micellar water content and reducing the I1/I3 ratio, which may result in a shape change of the micelles (sphere to rod-like) [46–48]. Similarly, the IE/IM ratio in SDS micelle increased sharply from DPC concentrations of 0.5 to 30.0 mmol L−1, indicating that excimer formation appeared to increase with DPC concentration. The surface-active properties of DPC [29] could improve the Γcmc of the SDS micelles. The high Γcmc values indicate that the micelles consisted of both DS− and DP+ monomers, resulting in the formation of mixed micelles, which could lead to shape changes from spherical to rod-like with increased DPC concentration. Interestingly, changes in the SDS micelle shape in the presence of amphiphilic cation phenothiazine drugs have also been reported [37]. 3.9. Effect of DPC on clotrimazole binding and encapsulation efficiency As mentioned above, the micellization and adsorption properties of SDGL and SDS were increased in the presence of DPC because of the synergistic interaction between SDGL or SDS and DPC and using DPC as an organic counterion had a significant effect on the micellar shape. Thus, the effect of DPC in SDGL or SDS micelles on the binding and encapsulation efficiency of the poorly water-soluble drug CLO was investigated.

A. Srivastava et al. / Journal of Molecular Liquids 300 (2020) 112288

9

Fig. 5. (A) Change in fluorescence intensity ratio of the first (373 nm) and third (384 nm) vibronic peaks of pyrene (I1/I3) and (B) Pyrene excimer (IE = 440 nm)/monomer (IM = 393 nm) fluorescence intensity ratio in sodium dilauramidoglutamide lysine (SDGL, (square)) and sodium dodecyl sulfate (SDS, (circle)) micelles as a function of increasing concentration of diphenhydramine hydrochloride (DPC). The solid line just guided the data trend for these systems. Relative standard uncertainties, ur for I1/I3 and IE/IM ratio = ±5%.

The Kb value of CLO for SDGL and SDS micelles were determined by UV absorption in the absence and presence of DPC (0.5–5.0 mmol L−1), as shown in Figs. S7 and S8. The characteristic UV–vis wavelength of CLO in the SDGL and SDS micelles was red-shifted from 260 to 272 nm, respectively, with increasing DPC concentration. To determine the binding constant under these conditions, we selected the characteristic

wavelength of 270 nm. We have previously reported similar observations for the DPC and sodium deoxycholate system [29]. A red-shift of ca. 12 nm is indicative of attractive interactions between CLO and surfactant micelles containing DPC. The addition of DPC to the SDGL or SDS micellar system increased the hydrophobicity of the micellar environment, resulting in enhanced of CLO encapsulation. However, errors

Fig. 6. Plots (A1–5) sodium dilauramidoglutamide lysine (SDGL) - Diphenhydramine hydrochloride (DPC) according to Eq. (6) showing the variation of 1 / (A − Aw) with 1 / (c − c0)Nm. The solid red line showed the linear fitting used to determine the Kb from the intercept and slope ratio. Plots (B1–5) SDGL-DPC shown the variation of micelle mean occupancy (estimated from the absorbance data) with micelle concentration. The solid red line showed the exponential fitting used to determine the i0 from the empirical equation (as shown in Table S1). The CLO and DPC concentration was given in the inset. Relative standard uncertainties, ur was ±5%. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

10

A. Srivastava et al. / Journal of Molecular Liquids 300 (2020) 112288

in the recorded intensity (the flat line at 270 nm) observed in the UV experiment were obtained at high DPC concentrations (N5.0 mmol L−1 DPC). Also, the Kb values (Nm = 1.0) were determined using Eq. (6) with a 1:1 ratio between the substance and the micelle. The Kb values of CLO are shown in Table 3 and Figs. 6 and 7(A1–5). The Kb values of CLO (c N c0) in SDGL and SDS micelles alone were 2.13 and 1.62, respecNm tively. Similarly, the Km values of CLO in SDGL and SDS alone b = Kbn were 3.24 and 3.46 at the cmc. Interestingly, the Km b values of CLO were greater than those for Kb. In SDGL and SDS mi−1 celles, the values of Kb and Km b of CLO decreased from 0.5 to 5 mmol L DPC concentration, as shown in Table 3. As discussed above, DP+ interacted more strongly with the SDGL micelles than the SDS micelles, and the presence of DP+ in the SDGL and SDS micelles increased the synergistic interactions with CLO. As a result, in the presence of various concentrations of DPC, the SDGL micelles have higher Kb and Km b values than the SDS micelle. Possibly, the SDGL micellar environment was hydrophobic, so CLO was solubilized into the micellar core of SDGL micelle. On the other hand, the SDS micelles are larger but have lower binding values, which indicates that the CLO molecules were solubilized in the Stern layer of the SDS micelles. The values of i (i = [Db]/[M]) from Eq. (7) were used to determine the mean occupancy of CLO in the micelle to verify the encapsulation of CLO in the SDGL and SDS micelles. Similarly, i decayed for CLO with increase in SDGL/SDS concentration. Next, an exponential equation (Eq. (7)) was fitted to the observed data, as shown in Figs. 6 and 7 (B1–5), which yielded i0 for CLO in SDGL and SDS micelles with increasing DPC concentration. The i0 values are shown in Table 3. Interestingly, the i0 value increased from 0.5 to 5.0 mmol L−1 DPC for both SDGL and SDS micelles. For the SDS micelles, the i0 value (Table 3) was more than that of the SDGL micelles. In the absence and presence of DPC in the aqueous surfactant solution, i0 can be used to estimate the

encapsulation effectiveness of CLO using SDGL and SDS. Fig. S10 and Table 4 shows that the CLO encapsulation efficiency increased with increase in DPC concentration. For example, the i0 values for CLOs using SDGL and SDS in the absence and presence of 5.0 mmol L−1 of DPC were 73.32 and 293.1 (absence) and 119.6 and 440.9 (presence), respectively. Similarly, in the absence and presence of 5.0 mmol L−1 of DPC, the CLO encapsulation efficiencies with SDGL and SDS were 19.61% and 47.51% (absence) and 25.45% and 69.54% (presence), respectively. The value of i0 might depend not only on the cmc of SDGL and SDS but also on the size and shape of the micelles. As mentioned above, SDGL has better micellization properties, yielding small (spherical) micelles in the presence of DPC, resulting in lower CLO i0 and encapsulation values. In contrast, SDS interacts less with DPC, but the bigger (rod-like) micelles result in higher CLO i0 and encapsulation values. This is consistent with the value of i0, which correspond with the encapsulation efficiency values. 4. Conclusion This work highlights the use of the amphiphilic drug DPC as an organic counterion. DPC significantly reduced the cmc of SDGL and SDS in aqueous media. Compared to single ionic surfactants, the doublechain Gemini surfactant shows greater counterion binding values. The negative values of ΔG°mic were higher for SDGL than for SDS with the increase in DPC. This shows that the presence of mixed counterions can improve the electrostatic interaction and decrease the repulsive interaction between surfactant head groups. The Kb values were controlled by both hydrophobic and electrostatic interaction because SDGL, which has a double chain, could bind more DP+ molecules on the above cmc than a single SDS chain. Interestingly, at the cmc, the Km b values of DPC in SDS micelle were higher than those of the SDGL

Fig. 7. Plots (A1–5) sodium dodecyl sulfate (SDS) - diphenhydramine hydrochloride (DPC) according to Eq. (6) showing the variation of 1 / (A − Aw) with 1 / (c − c0)Nm. The solid red line showed the linear fitting used to determine the Kb from the intercept and slope ratio. Plots (B1–5) SDS-DPC shown the variation of micelle mean occupancy (estimated from the absorbance data) with micelle concentration. The solid red line showed the exponential fitting used to determine the i0 from the empirical equation (as shown in Table S1). The CLO and DPC concentration was given in the inset. Relative standard uncertainties, ur was ±5%. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

A. Srivastava et al. / Journal of Molecular Liquids 300 (2020) 112288

micelle. At the cmc, the Km b values were higher than Kb values, which depended on the adsorption properties of both SDGL and SDS because the SDS Γcmc values were higher than those of SDGL at various DPC concentrations. In addition, the UV absorbance data were used to determine the mean number of DP+ ions per micelle (i0), revealing that the SDS micelles had higher i0 values than the SDGL micelles. The UV transmittance and DLS results for SDGL and SDS showed that different micelle types were formed with different concentrations of DPC. The pyrene probe study revealed that the decreased I1/I3 ratio and increased IE/IM ratio predict the micellar shape change in increasing DPC concentration. In addition, the use of DPC improves the binding behavior of the poorly water-soluble drug CLO in aqueous media. The mean ion occupancy per micelle (i0) values were determined as a measure of the CLO encapsulation efficiency in the SDGL and SDS micelles with increasing DPC concentration. In summary, we conclude that amphiphilic drugs can be used as organic counterions in drug delivery system to improve drug– surfactant formulation, but these systems require further study. CRediT authorship contribution statement Anirudh Srivastava: Conceptualization, Investigation, Data curation, Writing - original draft.Hiromasa Uchiyama: Conceptualization, Writing - review & editing.Hideki Imano: Investigation, Data curation, Writing - review & editing.Hiroshi Satone: Formal analysis, Writing original draft.Kenji Iimura: Formal analysis, Writing - original draft. Kazunori Kadota: Conceptualization, Writing - review & editing.Yuichi Tozuka: Conceptualization, Writing - review & editing. Acknowledgements We thank Asahi Kasei Chemicals Co. Ltd. for the kind gift of SDGL. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi. org/10.1016/j.molliq.2019.112288. References [1] D. Kumar, S. Hidayathulla, M.A. Rub, Association behavior of a mixed system of the antidepressant drug imipramine hydrochloride and dioctyl sulfosuccinate sodium salt: effect of temperature and salt, J. Mol. Liq. 271 (2018) 254–264. [2] D. Kumar, M.A. Rub, Interaction of ninhydrin with chromium-glycylglycine complex in the presence of dimeric Gemini surfactants, J. Mol. Liq. 250 (2018) 329–334. [3] M.L. Corrin, W.D. Harkins, The effect of salts on the critical concentration for the formation of micelles in colloidal electrolytes, J. Am. Chem. Soc. 69 (1947) 684–688. [4] K. Ismail, Influence of counterions on the aggregation of ionic surfactants and the Corrin-Harkins equation, J. Indian Chem. Soc. 95 (2018) 1471–1480. [5] I.M. Umlong, K. Ismail, Micellization behaviour of sodium dodecyl sulfate in different electrolyte media, Colloids Surf. A Physicochem. Eng. Asp. 299 (2007) 8–14. [6] J. Dey, J. Bhattacharjee, P.A. Hassan, V.K. Aswal, S. Das, K. Ismail, Micellar shape driven counterion binding. Small-angle neutron scattering study of AOT micelle, Langmuir 26 (2010) 15802–15806. [7] T. Mukhim, J. Dey, S. Das, K. Ismail, Aggregation and adsorption behavior of cetylpyridinium chloride in aqueous sodium salicylate and sodium benzoate solutions, J. Colloid Interface Sci. 350 (2010) 511–515. [8] R. Abdel-Rehem, The influence of hydrophobic counterions on micellar growth of ionic surfactants, Adv. Colloid Interf. Sci. 141 (2008) 24–36. [9] A. Srivastava, K. Ismail, Binding of phenol red to cetylpyridinium chloride at air solution and micelle–solution interfaces in aqueous ethylene glycol media, Colloids Surf. A Physicochem. Eng. Asp. 462 (2014) 115–123. [10] U. Thapa, J. Dey, S. Kumar, P.A. Hassan, V.K. Aswal, K. Ismail, Tetraalkylammonium ion induced micelle-to-vesicle transition in aqueous sodium dioctylsulfosuccinate solutions, Soft Matter 9 (2013) 11225–11232. [11] M. Akram, S. Yousuf, T. Sarwar, Kabir-ud-Din, Micellization and interfacial behavior of 16-E2-16 in presence of inorganic and organic salt counterions, Colloids Surf. A Physicochem. Eng. Asp. 441 (2014) 281–290. [12] P. Mukerjee, K.J. Mysels, P. Kapauan, Counterion specificity in the formation of ionic micelles-size, hydration, and hydrophobic bonding effects, J. Phys. Chem. 71 (1967) 4166–4175. [13] E.W. Anacker, A.L. Underwood, Organic counterions and micellar parameters. Nalkyl carboxylates, J. Phys. Chem. 85 (1981) 2463–2466.

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