Supramolecular systems based on gemini surfactants for enhancing solubility of spectral probes and drugs in aqueous solution

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Supramolecular systems based on gemini surfactants for enhancing solubility of spectral probes and drugs in aqueous solution A.B. Mirgorodskaya a,b , L. Ya Zakharova a,b,∗ , E.I. Khairutdinova a , S.S. Lukashenko a,b , O.G. Sinyashin a,b a A.E. Arbuzov Institute of Organic and Physical Chemistry of Kazan Scientific Center of Russian Academy of Sciences, 8, ul. Arbuzov, Kazan, 420088, Russian Federation b Kazan National Research Technological University, 68, ul. K. Marx, Kazan, 420111, Russian Federation

h i g h l i g h t s

g r a p h i c a l

a b s t r a c t

• Novel dicationic surfactants bearing • • • •

morpholinium moieties are synthesized. Morpholinium geminis show superior solubilization activity toward a drug. Solubilization of a drug results in pKa shift. Mutual influence of the guest/host properties occurs upon the solubilization. Multifactor mechanism of the drug solubilization is realized.

a r t i c l e

i n f o

Article history: Received 31 January 2016 Received in revised form 11 July 2016 Accepted 21 July 2016 Available online xxx Keywords: Morpholinium surfactant Gemini Solubilization Thymolphthalein Indomethacin

a b s t r a c t Herein, novel dicationic surfactants bearing morpholinium moieties in polar group, 14-s-14 Mor (s = 4, 6, 8, 10) are synthesized, and their aggregation behavior is studied and compared with reference surfactants, single-head morpholinium surfactant Mor-14, typical gemini with ammonium head group and dicationic surfactants with heterocyclic polar fragment. Geminis studied are found to exhibit superior solubilization capacity toward a pH indicator thymolphthalein and an inflammatory drug indomethacin, exceeding that of reference amphiphiles. The solubility of the probes is contributed by multifactor mechanism involving the solubilization in nonpolar core of micelles and periphery electrostatic interaction between micellar surface charge and ionic moieties of the drug. Mutual influence of the components occurs on their properties, including pKa shift of ionogenic groups of a guest molecule and decrease in critical micelle concentration of geminis. © 2016 Elsevier B.V. All rights reserved.

1. Introduction ∗ Corresponding author at: 8, ul.Akad. Arbuzov, Kazan, 420088, Russian Federation. E-mail addresses: [email protected], [email protected] (L. Ya Zakharova).

Organized systems based on surfactants find numerous applications in medicine, pharmacy, food industry, analytical assays, catalysis, and so on [1–7] due to their ability of incorporating

http://dx.doi.org/10.1016/j.colsurfa.2016.07.065 0927-7757/© 2016 Elsevier B.V. All rights reserved.

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s = 4 (14-4-14 Mor), 6 (14-6-14 Mor), 8 (14-8-14 Mor), 10 (14-10-14 Mor), Alkanediyl-α,ωbis(tetradecylmorpholinium bromide)

Hexanediyl-α,ω-bis(dimethylammonium bromide) (14-6-14)

Tetradecylmethylmorpholinium bromide (Mor-14)

O CH3

O

CH3

H3C HO

CH3 H3C

OH CH3

Thymolphthalein (TP)

Indomethacin (Ind)

Scheme 1. Structural formulas of compounds used.

the low-polarity compounds, thereby modulating the properties of them including stability, reactivity, acid-base equilibria, color, etc. [8–15]. Incorporation of these hydrophobic substances in nonpolar interior of surfactant micelles results in marked increase of their solubility in polar media. Therefore this phenomenon is generally termed as solubilization and quantitatively described by partition coefficients characterizing the molar ratio of a compound occurring in micelles and dispersion phase [16–19]. Solubilization efficacy is determined by a variety of factors, such as hydrophilic-lipophilic property of surfactants, morphology of aggregates, occurrence of additives, solution pH, and the nature of the solubilizate. One of the most significant factors is the structure of surfactants, in particular, charge character of head group, dimension of hydrophobic domain formed, the possibility of specific interactions substrate-micelle, etc. [19–21]. Due to technological progress and concomitant ecological problems researchers need to take into account ever increasing criteria for the surfactant systems design and application. The occurrence of solubilization activity within low concentration range and mild conditions, high solubilization capacity, high selectivity, low toxicity, polyfunctionality of systems, etc. are of particular importance in the case of application of surfactant systems for the drug delivery in medicine and pharmaceutical industry [22–25]. Therefore, in pharmacy much attention is paid to low toxic nonionic surfactants Tween 20, Tween 80, Triton-X-100, Tyloxapol and others [26–30]. Meanwhile, ionic surfactants may exhibit superior solubilization efficacy compared to that of nonionic analogs due to the contribution of electrostatic mechanism. Besides, additional interactions can be involved, provided that functional groups occur capable of H-bonding or stacking effects. Noteworthy, cationic surfactants show high affinity to a variety of biological molecules and surfaces, e.g. they are very effective in transdermal route for drug delivery [31,32], as well as in ocular administration due to the electrostatic affinity of formulated drugs toward negatively charged mucin residues, thereby increasing the resistance time [33,34]. Thus, the application of cationic surfactants as drug carriers assumes that the balance between high efficiency of formulations and their safety should be achieved. In the light of foregoing, gemini dicationic surfactants are very promising candidates for the design of drug delivery vehicles. Due to their enhanced hydrophobicity, i.e. occurrence of two long-chained alkyl tails bridged with spacer fragment, gemini surfactants are characterized by low critical micelle concentration

(cmc) and large hydrophobic domain, which allows them to show effective solubilizing activity within low concentration range. Typical gemini surfactants denoted as m-s-m (here m is the number of carbon atoms in alkyl tail; s is the number of carbon atom in polymethylene spacer) are mostly studied [35,36]. Significantly, geminis exhibit diverse morphological behavior that can be tuned with both the variation in the molecule structure and external stimuli [37–40]. This is of great importance from the viewpoint of controlling the binding/release behavior of formulated drugs. To date a large variety of publications are available on the aggregation of dicationic geminis in aqueous solutions [35,36,41,42]. Most significantly, high research activity directed towards application of geminis in different segments of nano- and biotechnologies occurs. The use of geminis for the solubilization of hydrophobic aromatic hydrocarbons, n-alkylbenzenes, exemplified by naphthalene, pyrene, dyes, spectral probes are documented [43–49]. Much attention is paid to the design of nonviral vectors for gene delivery based on dicationic surfactants [50–53]. Application of solutions of dicationic surfactants as reaction media is intensively explored as well [54–61]. Design of novel surfactant molecules with functional groups capable of multi-centered interactions with solutes, the structure-activity correlation, and factors responsible for the practically important properties of the systems are the focus of these studies. These problems remain challenging and need further efforts to be solved. Herein, novel dicationic surfactants with the morpholinium moiety in polar group (14-s-14 Mor) are synthesized, their aggregation behavior and solubilization capacity toward a spectral probe thymolphthalein and a drug indomethacin are studied. Properties of dicationic morpholinium surfactants 14-s-14 Mor are compared with monocationic morpholinium analog Mor-14 and typical gemini with ammonium head group m-s-m. Structural formulas of surfactants studied are given in Scheme 1.

2. Methods and materials 2.1. Materials Alkanediyl-␣,␻-bis(tetradecylmorpholinium bromide) were obtained by the interaction of tetradecylmorpholine with ␣,ωdibromoalkane in acetonitrile (reflux for 48 h) followed by double recrystallization from ethyl acetate, with the yield of 28–35%. The

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structure of the compounds synthesized was confirmed by elemental analysis, IR- and NMR-spectroscopies data. 2.2. Butanediyl-1,4-bis(tetradecylmorpholinium bromide) C40 H80 N2 O2 Br2 (783.12); calculated (%): C 61.35; H 10.55; N 3.57; Br 20.40; found (%): C 61.30; H 10.78; N 3.52; Br ˜ IR (KBr, ␯, cm−1 ): 2953, 2919, 2851, 1472, 20.22. mp 196–197◦ N. 1379, 1266, 1125, 1052, 948, 888, 720, 639. 1 H NMR (600 MHz, CHCl3 -d, ␦, p.p.m J/Hz): 0.89 [t, 6Н, 2х N+ CН2 CН2 (CН2 )11 CН3 , J = 6.6]; 1.27–1.40 [br.m, 44Н, 2х N+ CН2 (CН2 )11 CН2 CН3 ]; 1.82 [s, 4Н, 2х N+ CН2 (CН2 )11 CН2 CН3 ], 2.22 [s, 4Н, N+ CН2 (CН2 )2 CН2 N+ ]; 3.53–3.57 [m, 8Н, 2х N+ (CН2 )2 ], 3.82–3.85 [m, 4Н, 2х N+ CН2 sp.]; 3.95–4.03 [m, 8Н, 2х O(CН2 )2 ]; 4.27–4.30 [m, 4Н, 2х N+ CН2 CН2 (CН2 )11 CН3 ]. 2.3. Hexanediyl-1,6-bis(tetradecylmorpholinium bromide) C42 H86 N2 O2 Br2 (810.96); calculated (%): C 62.19; H 10.68; N 3.45; Br 19.70; found (%): C 62.45; H 10.79; N 3.30; Br 19.53. mp 217–218 ◦ C. IR (KBr, ␯, cm−1 ): 2933, 2918, 2850, 1468, 1378, 1118, 1048, 911, 899, 851, 722, 641. 1 H NMR (600 MHz, CHCl -d, ␦, p.p.m J/Hz): 0.89 [t, 6Н, 3 2х N+ CН2 CН2 (CН2 )11 CН3, J = 6.9]; 1.27–1.39 [br.m, 44Н, 2х N+ CН2 (CН2 )11 CН2 CН3 ]; 1.69 [m, 8Н, (CН2 )4 sp]; 2.02 [s, 4Н, 2х N+ CН2 (CН2 )11 CН2 CН3 ]; 3.57–3.65 [m, 8Н, 2х N+ (CН2 )2 ], 3.83 [s, 4Н, 2х [N+ (CН2 )2 sp]; 3.96–3.98 [m, 8Н, 2х O(CН2 )2 ]; 4.22–4.25 [m, 4Н, 2х N+ CН2 CН2 (CН2 )11 CH3 ]. 2.4. Octanediyl-1,8-bis(tetradecylmorpholinium bromide) C44 H90 N2 O2 Br2 (838.98); calculated (%): C 62.99; H 10.81; N 3.34; Br 19.05; found (%): C 62.73; H 10.99; N 3.36; Br 19.22. mp 167–168 ◦ C. IR (KBr, ␯, cm−1 ): 2953, 2924, 2853, 1467, 1378, 1263, 1123, 1057, 899, 722, 639. 1 H NMR (600 MHz, CHCl3 -d, ␦, p.p.m J/Hz): 0.89 [t, 6Н, 2х N+ CН2 CН2 (CН2 )11 CН3 , J = 6.9]; 1.27–1.42 [br.m, 44Н, 2х N+ CН2 (CН2 )11 CН2 CН3 ]; 1.53 [s, 8Н, N+ CН2 CН2 (CН2 )4 CН2 CН2 N+ ];]; 1.75 [s, 4Н, 2х N+ CН2 (CН2 )11 CН2 CН3 ]; 1.89 [s, 4Н, N+ CН2 CН2 (CН2 )4 CН2 CН2 N+ ]; 3.56–3.67 [m, 8Н, 2х N+ (CН2 )2 ], 3.81–3.84 [m, 4Н, N+ CН2 CН2 (CН2 )4 CН2 CН2 N+ ]; 3.94–4.00 [m, 8Н, 2х O(CН2 )2 ]; 4.16–4.20 [m, 4Н, 2х N+ CН2 CН2 (CН2 )11 CН3 ].

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2.6. Instruments and methods 2.6.1. Surface tension measurements The surface tension () measurements were made with K6 tensiometer (Krüss) by the du Noüy ring detachment method at 25 ◦ C. Surfactant concentration was varied by adding concentrated surfactant solution, and the readings were noted after thorough mixing and temperature equilibration. The cmc values were determined as the concentration corresponding to the breakpoints in the ␥ vs. logarithm of surfactant concentration plots. 2.6.2. Conductivity measurements Conductivity measurements were performed using Inolab Cond 720 instruments at 25 ◦ C. The conductivity () versus surfactant concentration was plotted, and the cmc was obtained from the concentration corresponding to the intersection of  extrapolated from the experimental values below and beyond the cmc. Fraction of counter-ion binding was calculated based on the slope of the dependence in pre- and post micellar regions. 2.6.3. Spectrophotometric measurements UV–vis spectra of samples studied were recorded in 1 or 0.10 cm quartz cells using Specord 250 Plus (Analytik Jena) spectrophotometers equipped with a thermostated cell unit. The extinction coefficient (␧) of a probe was determined from the optical density (D), measured at the wavelength corresponding to the absorption maximum from the relation ␧ = D/LC, where C is a concentration of the probe, and L is the path length. The average values of three to five measurements were used, with the reproducibility being of ±0.05. The apparent pKɑ value (рKɑ,app ) of thymolphthalein was calculated on the basis of its absorbency at different pH values according to the Henderson-Hasselbalch equation: рKɑ,app = pH + log[neutralform]/[anionicform] The solubilizing capacity of micellar systems toward thymolphthalein (or indomethacin) was determined for its saturated solution as follows. The excess of a crystalline probe was placed in the surfactant solution at neutral pH, stirred vigorously for 1 h and then equilibrated for 48 h at 25 ◦ C. The undissolved probe was filtered, and the filtrate was put to a cuvette, after which optical density at the maximum absorption (280 nm for thymolphthalein and 327 nm for indomethacin) was measured. The error of all experiments was <4%.

2.5. Decanediyl-1,10-bis(tetradecylmorpholinium bromide) 3. Results and discussion C46 H94 N2 O2 Br2 (867.08); calculated (%): C 63.67; H 10.92; N 3.23; Br 18.43; found (%): C 63.54; H 11.05; N 3.21; Br 18.32. mp 154–156 ◦ C. IR (KBr, ␯, cm−1 ): 2924, 2853, 1467, 1378, 1259, 1123, 1057, 964, 895, 722, 640. 1 H NMR (600 MHz, CHCl -d, ␦, p.p.m J/Hz): 0.89 [t, 6Н, 2х 3 N+ CН2 CН2 (CН2 )11 CН3 , J = 6.7]; 1.27–1.39 [br.m, 56Н {44H, 2х N+ CН2 (CН2 )11 CН2 CН3 + 12H, N+ CН2 (CН2 )3 (CН2 )2 (CН2 )3 CН2 N+ }]; 1.75–1.83 [m, 8H, {4H, N+ (CН2 )4 (CН2 )2 (CН2 )4 N+ + 4H, 2х N+ CН2 (CН2 )11 CН2 CН3 }]; 3.59-3.68 [m, 8Н, 2х N+ (CН2 )2 ]; 3.79–3.90 [m, 8Н, 2х O(CН2 )2 ]; 4.09–4.15 [m, 4Н, 2х N+ CН2 CН2 (CН2 )11 CН3 ]. Tetradecylmethylmorpholinium bromide was prepared through reaction of methylmorpholine with tetradecyl bromide, in analogy with [62] followed by re-crystallization of reaction mixture; mp 215 ◦ C. Commercially available indomethacin, thymolphthalein and bromoalkanes (all from Sigma-Aldrich) were used without additional purification. Water purified with the Milli-Q Water Purification System was used for the sample preparation.

3.1. Aggregation behavior of gemini 14-s-14 Mor in aqueous solutions In present paper, the principal method for the cmc determination of 14-s-14 Mor is the surface tension measurements. Conductivity measurements are involved to compare results of different techniques, as well as to estimate the degree of counterion binding ␤ (␤ = 1-␣, where ␣ is the fraction of the counter-ion dissociation equal to the ratio of slopes of linear sections of the dependence below and above the cmc). Results obtained are presented in Figs. 1 and 2 and summarized in Tables 1 and 2. Aggregation and morphological behavior of dicationic surfactants attracted much attention, with the hydrophobicity, spacer length and structure of head groups varied [35,37,65–68]. While an increase in alkyl chain length definitely results in a decrease in cmc values [35], the variation in structure of spacer fragment may affect the aggregation properties in different manner [37]. For typical gemini surfactants with flexible polymethylene spacer

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Table 1 Values of cmc and counterion binding degree for geminis 14-s-14a. Surfactant

104 cmc, М (tensiometry)

104 cmc, М (conductometry)

Kraft temperature, ◦ C

fraction of dissociated counterions, ␣ (counterion binding degree, ␤) a

14-4-14 Mor 14-6-14 Mor 14-8-14 Mor 14-10-14 Mor 14−6-14 [63]

1.9 1.7 0.9 1.56 2.2

1.77 2.47 1.98 1.86 –

18 – 14 17

0.31 (0.69) 0.25 (0.75) 0.36 (0.64) 0.37 (0.63) 0.33 (0.67)

a

For Mor −14 cmc = 0.004 М [62].

Table 2 Maximum surface excess (max ), the area per surfactant molecule (Amin ), standard free micellization energy Gm and standard free adsorption energy Gad calculated on the basis of tensiometric data for 14-s-14 gemini surfactants. Surfactant

 max 106 , mol m−2

Amin , nm2

 cmc, mN m−1

Gm , kJ mol−1

Gad , kJ mol−1

14-4-14 Mor 14-6-14 Mor 14-8-14 Mor 14-10-14 Mor 14−4-14 [64]

1.11 0.70 0.76 0.72 1.69

1.5 2.4 2.2 2.3 0.98

44.3 46.4 43.3 45.6 41

36.6 31.7 35.2 33.1

60.2 68.2 72.9 33.1

Fig. 1. Surface tension isotherms of aqueous solutions of 14-s-14 Mor; 25 ◦ C.

16-s-16 maximum cmc value is observed for s = 5–6 [37,66]. The same trend occurred in the case of hydroxyethylated gemini [67]. On the other hand, cmc is reported to slightly decreased with an increase in s value for bispyridinium surfactants bearing dodecyl tails [69]. According to literature data changes in cmc with the variation in spacer length may result from conformational peculiarity of short (s < 6) and long (s ≥ 6) polymethylene chains, which in turn is responsible for the different packing mode. Data in Table 1 reveal that cmc of gemini family studied varies within the range from 0.1 to 0.25 mM and little changes with the variation in spacer length, which probably emphasizes the minor role of spacer fragment compared to contribution of hydrophobic tails to the aggregation mechanism. Noteworthy that counter-ion binding degree shows steady decrease with the increase in s value, thereby following the reported tendency for typical m-s-m surfactants [37] and their hydroxyethylated analogs [67]. At the same time, non-monotonous

Fig. 2. Specific conductivity of aqueous solutions of dicationic morpholinium surfactants as function of their concentration; 25 ◦ C.

change in ␤ values are documented for 16-s-16 gemini series [66] and bispyridinium surfactants [69], with a minimum in counter-ion binding occurring at s = 8 and 4 respectively. Additional information may be obtained from the quantitative treatment of surface tension isotherms based on Eqs. S1–S4. One of the most informative values obtained is the minimum surface area per a head group. Generally, this parameter smoothly increases with the length of polymethylene spacer [37], which is connected with its location on the periphery of aggregates, thereby preventing head groups from the compact packing. Data in Table 2 demonstrate the same tendency. As a whole, Amin values obtained herein are in good agreement with those reported in Refs. [37,68,70], while are somewhat higher compared to 14-s-4 gemini [70]. The same is true for the value of ␥cmc ranged as 41–46 mN m−1 (Fig. 1). For comparison, ␥cmc changed within the range of 38–43 mN m−1 for

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Table 3 Values of cmc, solubilization capacity S of 14-s-14 Mor and reference compounds toward TP and Ind determined by spectrophotometry, and pKa values of TP in micellar solutions; 25 о C. 104 × cmca , M

Surfactant

14−6-14 14-4-14 Mor 14-6-14 Mor 14-8-14 Mor 14-10-14 Mor Mor −14 a b

2.2 2.3 1.6 2.7 38

TP

Ind

b, L mol−1 cm−1

S

рKɑ b

b, L mol−1 cm−1

S

270 280 446 229 119 20.8

0.042 0.044 0.070 0.036 0.019 0.0032

9.70 9.70 10.10 10.20 10.25 9.45

1855 [88] 2855 2887 2455 2403 573

0.320 [88] 0.492 0.497 0.423 0.414 0.099

cmc values derived from the initial section of absorbency vs surfactant concentration plots for saturated solutions of TP. pKa of TP in water 9.7 [71].

D, a.u.

1.0

is typically higher compared to single head analogs and increases with alkyl chain length and polarity of head groups, although deviations from these regularities are documented as well [37,67]. TK values of 14–18 ◦ C obtained herein (Table 1, Fig. S1) are in agreement with literature data for m-s-m series, e.g. TK varies from ca. 50 to 10 ◦ C for s ranged as 2–12 [37]. There is no clear dependence of TK on the spacer length, with non-monotonous character of changes observed. Similar non-monotonic TK vs s dependence is obtained herein. Again, in analogy with reported data [37] we failed to reveal any correlation between TK and Tm , although it is well documented for single head surfactants. Thus, it was shown that dicationic morpholinium surfactants self-assembly at tenfold lower concentrations compared to monocationic analogs, which allows us to expect that they can show solubilization activity within micromolar concentration range. Herein, solubilization properties of 14-s-14 geminis were studied toward two hydrophobic substances, spectral probe thymolphthalein and anti-inflammatory drug indomethacin.

0.8 1

0.6

0.4 2

0.2

0.0

260 280 300 320 340 360 380 λ, nm

Fig. 3. UV–vis spectra of TP in aqueous 14-6-14 Mor solution (0.002 M) at TP concentration of 0.1 (1) and 0.04 (2) mM; pH 6.5; 25 ◦ C.

14-s-14 gemini [70], 42–46 mN m−1 for bispyridinium surfactants [69] and 40–42 mN m−1 for other geminis with heterocyclic polar fragment [68]. 3.2. Krafft temperature measurements Specific conductivity measurements (Fig. 2) strongly support the association behavior of gemini 14-s-14 Mor revealed by tensiometry technique. It is noteworthy that electrical conductivity is determined by concentration of ionic species, i.e. surface active ions and counter-ions. Therefore, counter-ion binding degree is one of key factors controlling the conductivity. However, the major factor responsible for the conductivity value is the cmc parameter that determines the concentration of monomeric surfactant molecules capable of disassociation entirely in water, thereby controlling the conductivity of samples. Thus the low cmc values of 14-s-14 family (around of ca. 0.1 mM, Table 1) resulted in rather low values of conductivity (ca. 30 ␮S/cm). The latter is much lower compared to e.g. dodecyl derivatives reported in Ref. [68]. Important parameter of ionic surfactants responsible for their micellar behavior is the Krafft temperature (TK ). Generally, Krafft temperature is determined by several factors, such as solubility of compounds, packing of molecules in solid phase (it can correlate with melting point, Tm ), counter-ion binding, which can affect the mobility of ionic carriers in solution, etc. For gemini surfactants TK

3.3. Solubilization of thymolphtalein Thymolphthalein (TP) is a hydrophobic pH indicator well soluble in organic media, with pH transition range around 9.3–10.5 which is widely used for analytical assays. It undergoes two-step dissociation in water with resulting pKa value of 9.7 [71–73]. Under experimental conditions (pH 6.5) TP is in its neutral (uncharged) form, and its electronic spectra have a maximum at 280 nm, with the intensity of the absorbency controlled by the concentration of TP (Figs. 3 and S2). Molar extinction coefficient of neutral form of TP (6400 L mol−1 cm−1 ) is practically unchanged upon transfer from water to gemini 14-s-14 Mor solutions. Based on spectral data collected under the variation of the concentration of morpholinium surfactants, limiting content of TP in micellar solutions at neutral pH is determined. This makes it possible to quantify and compare the solubilization capacity (S) of different micellar systems. Value S is determined by the molar ratio between the number of molecules solubilized and concentration of the surfactant micellized, which can be calculated as follows: S = b/ε, where b is the slope of dependence of absorbency on the surfactant concentration, and ε is exctinction coefficient. Fig. 4 shows spectra of saturated solutions of TP in the presence of gemini exemplified by 14-8-14 Mor with different surfactant concentrations. Fig. 5 summarizes changes in the maximal absorbency of TP at 280 nm with an increase in the surfactant concentration, which makes it possible to calculate solubilization capacity of micelles S (Table 3). Since TP is practically insoluble in water, the occurrence of the absorbency at 280 nm in the presence of surfactants is connected with their aggregation followed by the probe solubilization. Therefore, sharp increase in the absorbency (Fig. S3) reflects the onset of the micellization and is generally used for the cmc determination. As can be seen (Tables 1 and 3), cmc values obtained

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D, a.u.

D, a.u.

0.8

Csurf 10 mM

0.6

1.6

1.2 1.0 0.8 0.6

pH 13

1.4 D

6

1.2 1.0 0.8 0.6 0.4

pH 4

0.2 0.0

300

400

500

600

700 800 λ, nm

0.4

14-10-14 Mor 14-6-14Mor 14-4-14 Mor Mor -14

0.2

0.4

0.0

Csurf 0.05 mM

8

10

12

pH

Fig. 6. Absorbency of aqueous solutions of TP (0.015 mM) at 595 nm in the presence of geminis 14-s-14 Mor (3 mM) at different pH values; path lengh is 0.2 cm; 25 ◦ C. Inset shows TP (0.02 mM) spectra at different pH values in 14-8-14 Mor solution (3 mM); path lengh is 0.2 cm; 25 ◦ C.

0.2

0.0

6

260

280

300

320

340

λ, nm Fig. 4. UV–vis spectra of TP saturated solutions in the presence of different gemini 14-8-14 Mor concentrations; path length is 0.2 cm, рН 6.5, 25 ◦ C.

5

4

14-6-14Mor 14-4-14Mor 14-10-14Mor 14-8-14Mor

D/l

3

2

1

0 0.000

0.005

0.010

С14-s-14Mor, M Fig. 5. Absorbency of 14-s-14 Mor micellar solutions saturated with TP as function of surfactant concentration; ␭ = 280 nm, рН 6.5, 25 ◦ C.

from surface tension isotherms and solubilization curves are in good agreement. Comparison of S values in Table 3 reveals that solubilization capacity of gemini micelles increases by four times in the order 14-10-14 Mor <14-8-14 Mor <14-4-14 Mor <14-6-14 Mor, exceeding efficacy of typical geminis with ammonium head group and even more that of Mor-14 (Fig. S2 and Table 3). It should be mentioned that solubilization capacity increases in the same order as the binding degree of counter-ions, which can reflect a general trend of an increase in the aggregation numbers of micelles

and hence their hydrophobic domains, when ␤ increases, due to a decrease in electrostatic repulsion between head groups. Solubilization of organic compound bearing ionogenic groups in micellar solution generally results in the pKa shift [74–76]. In surfactant solutions, indicators are usually characterized by the effective dissociation constant, Ka,app that can be influenced by the surfactant concentration. In alkali solutions anionic form of TP appears, which is reflected in UV–vis spectra, namely two absorption bands occur at 390–395 nm and 595 nm with ␧ = 9500 and 39,000 L mol−1 cm−1 respectively (Fig. S4). Spectra of TP remain almost unchanged upon the transition from water to micellar solutions of dicationic surfactants. We registered and analyzed electronic spectra of TP in micellar solutions of 14-s-14 Mor and reference surfactants Mor14 and 14-6-14 under the pH varied (Fig. 6, Inset and S4), which allowed us to estimate pKa,obs by using the Henderson- Hasselbalch equation (Table 3). While this approach provides only effective pKa value, preventing from the true protolytic constants being derived, it is of practical interest, since elucidates the effect of gemini surfactants on the acid-base equilibria, including the effect of spacer length on the equilibrium shift. This effect modifies the pH transition range, especially in the case of gemini 14-10-14 Mor, which should be taken into account upon the titration of probes in micellar systems. Typically, cationic surfactants shift to the right acid-base equilibria, i.e. decrease pKa values due to electrostatic attraction of basic (anionic) forms of ionogenic compounds [20,60,74]. As can be seen from Table 3, unlike monocationic surfactant an unusual increase in pKa values is observed in the case of dimeric analogs. It should be commented that despite the fact, that thymolphthalein is widely used as a pH indicator its acid-base equilibria should be treated with care. It is known that depending on solution pH thymolphthalein can exist in different forms, i.e. uncharged, monoand dicationic forms. In addition, TP can take part in tautomeric equilibrium giving rise to lactonic form [71–73]. It is rather difficult task to differentiate single pKa values for each form by spectrophotometry due to the overlapping of their spectra. Analysis of spectral data with CLIP program makes it possible to calculate the values of pK1 = 9.8 and pK2 = 9.6 [77]. For comparison, рK1 и рK2 equal 9.22 and 10.26 for CTAB micellar solution. Importantly, different sites of location of spectral probe in micelle can occur, including micellar core, the palisade layer, in vicinity of head groups, and the so-called two-site location of substrates, with transferring of molecules from periphery to the dipper interior after the saturation of initial population [16,74]. The spectral data obtained strongly support the solubilization of

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Csurf 0.05 mM

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48 0.0

0 0.0000

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С14-s-14Mor, M Fig. 7. Absorbency of 14-s-14 Mor micellar solutions saturated with Ind as function of surfactant concentration; ␭ = 327 nm, pH 6.5, 25 ◦ C. Inset shows spectra of saturated Ind solutions in the presence of 14-8-14 Mor.

hydrophobic TP in micellar interior by the marked increase in absorbency beyond the cmc. 3.4. Solubilization of indomethacin Another substance studied is a non-steroid anti-inflammatory drug indomethacin (Ind). In spite of its superior efficacy, there are limitations preventing its wider application in pharmaceutical industry, e.g. side effects and especially poor water solubility. To overcome the latter, solubilization of Ind in micellar solutions can be helpful. This provides the way for the preparation of aqueous formulations based on Ind, increasing their bioavailability and decreasing the dosages of the drug. Therefore, the solubilization of Ind in gemini 14-s-14 Mor micelles has been studied as well. Concentration of Ind in samples can be easily monitored by the registration of UV- spectra, which are characterized with two absorption bands at 270 nm (␧ 13700 L mol−1 cm−1 ) and 327 nm (␧ 5800 L mol−1 cm−1 ) within the pH range from 4 to 11 (Fig. S5). In micellar gemini solutions a slight bathochromic shift is observed as compared to water, with the extinction coefficient almost unchanged. Noteworthy, the problem of the Ind solubility is widely studied, with the limiting value varied from 0.9 ␮g/mL to 77 ␮g/mL (from 0.0025 mM to 0.22 mM) [78–82]. This ambiguousness can be caused not only by experimental errors associated with measurements in low concentration range, but more likely with polymorphism of Ind. In Ref. [82] values of the solubility of different forms of the drug and their mixtures are summarized and discussed. Even small enriching the preparation with some of these forms can markedly influence results. In this study the limiting Ind concentration of 11 ␮g/mL (0.03 mM) was spectrophotometrically determined. Importantly, in aqueous solutions Ind can undergo hydrolytic cleavage through nucleophilic attack by hydroxide-ions toward amide group [83–86]; this process is effectively accelerates by cationic micelles [87,88]. Observed rate constant is shown to achieve the value of 2.5 10−4 s−1 in 14-6-14 micellar solution at pH 11, however hydrolysis is markedly inhibited at neutral pH [88],

40

1E-6

1E-5

1E-4

1E-3

С14-6-14 Mor, М Fig. 8. Surface tension isotherms of 14-6-14 Mor aqueous solution; single solution (1) and with 0.1 mM Ind added (2); 25 ◦ C.

thereby exerting zero effect on the measurement of solubility of Ind under these conditions. Fig. 7 and Figs. S6 and S7 show changes in absorbency of saturated solution of the drug depending on the surfactant concentration at pH 6.5. As can be seen almost zero solubility of Ind occurs below the cmc, while the addition even of 0.5 mM gemini results in tenfold increase in the water solubility. Data in Table 3 testify that solubilization capacity of 14-s-14 Mor is higher than that of typical gemini family with ammonium head group, and by five times higher compared to monocationic analog Mor-14. These trends are very similar to those observed for the TP solubilization, with the difference that much more effective solubilization of the drug occurs, and spacer length exerts no effect on the solubilization of Ind. This difference is probably connected with the additional contribution of electrostatic mechanism to the binding of Ind by micelles. Due to the presence of carboxyl group (pKa 4.5 [89]) Ind molecule is negatively charged at neutral pH and therefore shows high affinity toward cationic micelles. For this reason, the finer effects of spacer length are levelling in this case. Such effective interaction between micelle (host) and drug (guest) through electrostatic mechanism typically exerts mutual effects, changing properties of both partners. Therefore, aggregation behavior of gemini is studied in the presence of Ind. Tensiometry data (Fig. 8) strongly support this idea, namely, cmc value essentially decreases in the presence of the drug, which is exemplified by 14-6-14 Mor. As can be seen, cmc decreases from 0.17 mM to 0.075 mM with 0.1 M Ind added (Fig. 8). Very similar behavior is observed in the case of reference compound 14-6-14 (Fig. S8). It can be assumed that electrostatic interaction of anionic form of Ind with gemini micelles results in partially neutralization of the surface charge and decreases electrostatic repulsion of head groups, thereby favoring the micellization, i.e. decreasing cmc value. This phenomenon is rather similar to the effect of organic electrolytes [90–92]. Thus solubilization of hydrophobic compounds is characterized by multifactor mechanism involving

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both, incorporation of nonpolar molecules into micellar core and periphery electrostatic interactions of charged groups. From the viewpoint of potential application of geminis as drug nanocarriers, the influence of blood or serum ingredients on the aggregation and solubilization properties are of importance, which can be roughly modeled by the use of salt additives. These data are exemplified by 14-6-14 Mor sample (Figs. S9, S10). As expected, salt admixture in gemini resulted in a decrease in cmc from 0.17 mМ to 0. 024 mМ (0.01 M NaCl), while further increase to 0.157 М NaCl results in a zero effect. Solubilization power is slightly suppressed in the presence of salt (from 0.497 to 0.393 and 0.376 at 0.01 and 0.157 M NaCl respectively), although the solubilization occurs at lower surfactant concentration in the presence of salt. 4. Conclusions Novel dicationic surfactants 14-s-14 Mor (s = 4, 6, 8, 10) with morpholinium fragments in head group and different spacer length are synthesized, and their aggregation behavior is characterized with the variety of methods. Solubilization capacity of geminis toward a hydrophobic pH indicator thymolphthalein and an anti-inflammatory drug indomethacin is higher as compared to reference surfactants, conventional gemini 14-6-14 and monocationic counterpart Mor-14. An increase in the water solubility for these hydrophobic guests can be caused by multifactor mechanism involving both the solubilization of nonpolar molecules in micellar interior and electrostatic binding of charge fragments of solutes with the micellar surface. Importantly, mutual changes occur in the structural behavior and properties of both, guest molecules and micelles. Solubilization of thymolphthalein results in the pKa shift and changes in the pH transition range. Incorporation of the drug indomethacin in micellar interior results in tenfold increase in its concentration even at 0.5 mM surfactant concentration, thereby enhancing the bioavailability of the drug. In turn, the solubilization of the drug indomethacin is shown to decrease markedly cmc values of geminis. The combination of high efficacy of formulations with the low surfactant concentration used answers the green chemistry criteria and demonstrates practical potential of gemini family studied as drug carriers. Acknowledgements This work is supported by the Russian Science Foundation (grant no. 14-23-00073). Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.colsurfa.2016.07. 065. References [1] S.E. Poynter, A.M. LeVine, Surfactant biology and clinical application, Crit. Care Clin. 19 (2003) 459–472. [2] M.A. Mateescu, P. Ispas-Szabo, E. Assaad, Controlled Drug Delivery: the Role of Self-assembling Multi-task Excipients, Woodhead Publishing Ltd., 2014. [3] H. Abdelkader, A.W.G. Alani, R.G. Alany, Recent advances in non-ionic surfactant vesicles (niosomes): Self-assembly, fabrication, characterization, drug delivery applications and limitations, Drug Deliv. 21 (2014) 87–100. [4] L. Zakharova, A. Mirgorodskaya, G. Gaynanova, R. Kashapov, T. Pashirova, E. Vasilieva, Y. Zuev, O. Synyashin, Supramolecular strategy of the encapsulation of low molecular weight food ingredients, in: A.M. Grumezescu (Ed.), Encapsulations, Academic Press London, 2016, pp. 295–362. [5] K. Yamjala, M.S. Nainar, N.R. Ramisetti, Methods for the analysis of azo dyes employed in food industry—a review, Food Chem. 192 (2016) 813–824. [6] N.J. Buurma, Reactivity in organised assemblies, Annu. Rep. Prog. Chem. B 107 (2011) 328–348.

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Please cite this article in press as: A.B. Mirgorodskaya, et al., Supramolecular systems based on gemini surfactants for enhancing solubility of spectral probes and drugs in aqueous solution, Colloids Surf. A: Physicochem. Eng. Aspects (2016), http://dx.doi.org/10.1016/j.colsurfa.2016.07.065