Investigation of Physiological Properties of Transglycosylated Stevia

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B: Fluid Interfaces, Colloids, Polymers, Soft Matter, Surfactants, and Glassy Materials

Investigation of Physiological Properties of Transglycosylated Stevia with Cationic Surfactant and Its Application to Enhance the Solubility of Rebamipide Hiromasa Uchiyama, Anirudh Srivastava, Miki Fujimori, Koji Tomoo, Akihito Nakanishi, Mahamadou Tandia, Kazunori Kadota, and Yuichi Tozuka J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.8b07515 • Publication Date (Web): 09 Oct 2018 Downloaded from http://pubs.acs.org on October 12, 2018

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The Journal of Physical Chemistry

Investigation of Physiological Properties of Transglycosylated Stevia with Cationic Surfactant and Its Application to Enhance the Solubility of Rebamipide Hiromasa Uchiyama,† Anirudh Srivastava,† Miki Fujimori,† Koji Tomoo,‡ Akihito Nakanishi,§ Mahamadou Tandia,§ Kazunori Kadota,† Yuichi Tozuka†* †

Department of Formulation Design and Pharmaceutical Technology, Osaka University of

Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan ‡

Department of Biophysical Chemistry, Osaka University of Pharmaceutical Sciences, 4-20-1

Nasahara, Takatsuki, Osaka 569-1094, Japan § Toyo

Sugar Reﬁning Co., Ltd., 18-20 Koami-Cho, Nihonbashi, Chuo-ku, Tokyo 103-0016, Japan

Corresponding Author Yuichi Tozuka Department of Formulation Design and Pharmaceutical Technology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan Tel: +81-72-690-1218 Fax: +81-72-690-1218 E-mail: [email protected]

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ABSTRACT: The poor water solubility of rebamipide was enhanced by the mixed micelles of transglycosylated stevia (Stevia-G) and trimethylammonium chloride with varying carbon chain length (CnTAC, n = 14, 16, and 18). Fluorimetric, isothermal titration calorimetry (ITC) and dynamic light scattering techniques examined the aggregation properties of Stevia-G and CnTAC. The synergism was found between Stevia-G and CnTAC using the approaches of Clint and Rubingh's. The negative interaction parameter (average βm= −4.17, −5.47, and −7.07) and excess free energy (average ΔGºex = −2.47, −3.06, and −3.88 kJmol−1) increased with increasing chain length of CnTAC. The negative B1 values by the Maeda approach suggested that chain-chain interactions contribute to the formation of a mixed micelle. The solubilization of rebamipide in the mixed micelle was evaluated in the term of the molar solubilization ratio (MSR) and partition coefficient (Km). The Km from the Stevia-G/C16TAC system was highest at a low mole fraction of CnTAC (0.2–0.6). In conclusion, the solubilization of rebamipide was more favorable between Stevia-G and C16TAC, although the stability of the mixed micelle was enhanced by an increase in hydrophobicity of the longer chain lengths used in CnTAC.


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INTRODUCTION

In recent drug development, many drug candidates have poor solubility because of an increase in molecular weight and lipophilicity.

1

Therefore, formulation techniques to

improve their solubility have become increasingly important. There are various methods for improving solubility, such as the preparation of nanoparticles 2, self-emulsifying formulation 3, and amorphous formulation using water-soluble polymers. 4 Surfactants are also used in the pharmaceutical formulation to improve the dissolution of water-insoluble drugs.

5

The surfactant forms micelles in an aqueous solution at a critical concentration

known as the critical micelle concentration (cmc) 6, 7, resulting in the enhancement of the apparent solubility of the poorly soluble drug. The major problem in the use of surfactants as pharmaceutical excipients is their toxicity. 8 Therefore, the use of surfactants in drug formulation tends to be severely limited. There is an increasing interest in the use of mixed surfactant systems that contribute to the synergistic effects of a mixed surfactant solution. 9, 10 These synergic effects are the enhanced surface activity, wetting, foaming, detergency, and solubilization. Mixed


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micellar aggregates are composed of two or more different surfactants in equilibrium with the surfactant monomers. One of the most well-known mixed surfactant systems in the human body is that between bile salts and lecithin. The mixed micelle composed of bile salts and lecithin plays an important role in dissolving poorly water-soluble drugs in the intestine.

11

The micelles encapsulate a poorly water-soluble drug into the micellar

structure, which enhances its apparent solubility and increases oral absorption. There are some successful reports on applying a mixed surfactant system between a nonionic surfactant and anionic surfactant. 12, 13 The mixture of sodium lauryl sulfate as an anionic surfactant and alkyl polyglucoside as a nonionic surfactant exhibited a synergic effect that decreased the value of the cmc when compared to using just a single surfactant. The mixture improved the dissolution properties of an insoluble anti-inflammatory compound. We have reported the mixed micelle system using Stevia-G, transglycosylated stevia-derived from Stevia rebaudiana 14. Stevia-G is recognized as safe by the US Food and Drug Administration and has been shown to have no cytotoxicity to a Caco-2 cell. 15 Interestingly, Stevia-G has a surface-active property and could form micelles in an aqueous medium.

16, 17

By utilization of the micellar structure of Stevia-G, the apparent


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solubility and absorption of poorly soluble compounds could be enhanced. 18 Amorphous particles of Stevia-G and probucol prepared using the spray-drying method enhanced the absorption of probucol by up to 9.8-fold compared to untreated probucol. On the other hand, Stevia-G showed a higher cmc value compared to surfactants commonly used as pharmaceutical additives. The value of the cmc of Stevia-G is ca. 10 mM in aqueous media, which means that a large amount of Stevia-G is required to achieve an improvement in dissolution. The mixed surfactant system made it possible to decrease the amount of Stevia-G needed to enhance the apparent solubility of insoluble drugs compared to using Stevia-G alone. The mixed micellization of Stevia-G and the cationic surfactant lauryl trimethylammonium chloride (LTAC) enhanced the solubility of mefenamic acid in water. 14 Stevia-G has strong interactions with LTAC, and it formed a stable mixed micelle that has a lower cmc compared to Stevia-G. Further studies into the mixed micelle properties of Stevia-G with ionic surfactants are required for their use in pharmaceutical applications. The purpose of this study is to clarify the effect of the length of the side chain of the ionic surfactant on the formation of mixed micelles with Stevia-G. Owing to the importance


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of Stevia-G in increasing the solubility of poorly water-soluble compounds and its strong interaction with ionic surfactants, this work focused on the interactions of Stevia-G with a series of alkydecyltrimethylammonium chloride, CnTAC (n = 14, 16, and 18), derivatives with different chain lengths but the same polar headgroup. The critical aggregation or micelle concentration was determined by the fluorescence probe method. Rubingh's approach was used to evaluate the thermodynamic parameters of Stevia-G and CnTAC. Isothermal titration calorimetry (ITC) was used to evaluate the formation of mixed micelles from Stevia-G and the surfactants by studying the changes in enthalpy (ΔHmic), entropy (ΔSmic), and Gibbs energy (ΔGmic) of micellization, which is crucial to understanding the micellization process. The solubilization of rebamipide in the presence of the mixed aggregates of Stevia-G/CnTAC was evaluated regarding the molar solubilization ratio (MSR) and partition coefficient (Km). Rebamipide is a quinolone derivative drug used to treat gastric and gastric mucosal lesions in acute gastritis and in the acute exacerbation of chronic gastritis.

19–21

Rebamipide is an insoluble drug not only in polar solvents but

also in nonpolar solvents.


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EXPERIMENTAL SECTION

Materials. Stevia-G was provided by Toyo Sugar Refining Co. (Tokyo, Japan). Acetonitrile,

tetradecyltrimethylammonium

chloride

(C14TAC),

hexadecyltrimethylammonium chloride (C16TAC), and octadecyltrimethylammonium chloride (C18TAC) were purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). Rebamipide was kindly supplied by Towa Pharmaceutical Co., Ltd. (Osaka, Japan). Steady-State

Fluorescence

Measurements.

Steady-state

fluorescence

measurements were used to determine the cmc of the individual and mixed surfactant solutions. A Hitachi F-7000 fluorescence spectrophotometer was used with a quartz cuvette of 1 cm path length. Pyrene (1 μM) was used as a probe. The excitation wavelength was 335 nm, and the emission spectra were recorded over the range 350– 500 nm. The emission and excitation slit widths were fixed at 5.0 and 1.5 nm, respectively. 22–23

The fluorescence emission intensities of I1 and I3 were measured at wavelengths


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corresponding to the first and third vibronic bands located near 373 and 384 nm. The I1/I3 ratio is the so-called pyrene 1:3 ratio. Isothermal Titration Calorimetry (ITC). ITC analysis is very useful for the determination of the thermodynamic parameters such as Gibbs free energy, enthalpy, and entropy of micelle formation. The ITC experiments were performed using an iTC200 isothermal titration calorimeter (MicroCal, Malvern Panalytical, UK) at 25.0 °C with distilled water as the reference. The aqueous solutions (100 mM) of Stevia-G, CnTAC, and the mixtures of Stevia-G/CnTAC were prepared as a function of the mole fraction of CnTAC (0.2–0.8). They have injected a total of 80 times at intervals of 120 s, using a titration volume of 0.5 μL, into a 200 μL titration cell containing distilled water. Origin 7 software was used for data analysis. Dynamic light scattering method (DLS). The hydrodynamic size of the micelle and mixed micelle of Stevia-G, CnTAC, and the mixtures of Stevia-G/CnTAC was determined using a Nanotrac UPA-UT151 (Nikkiso Co.LTD, Japan) dynamic light scattering (DLS) instrument at 635 nm (20 mW He–Ne laser) and 90 scattering angle. Samples were filtered through a 0.22-μm membrane filter before measuring. The scattering intensity


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data were processed using the instrument software to obtain the hydrodynamic diameter and the size distribution of aggregates in each sample. During DLS measurements the temperature was maintained at 25 C using the built-in temperature control unit of the instrument. Solubility Test. The apparent solubility of rebamipide in 25 mL of distilled water was measured at 37 °C in triplicate. To test tubes containing 50 mg of the drug, mixed solutions of Stevia-G and CnTAC were added at molar fractions αCnTAC of 0, 0.2, 0.4, 0.6, 0.8, and 1.0 at a total concentration of 0–18 mM. The sample tubes were placed in a water bath for 24 h at 37 °C and shaken at 100 rpm. Before sampling, the samples were centrifuged at 4,000 rpm for 5 min. The supernatant was carefully withdrawn and filtered through a 0.2-μm filter and immediately assayed for drug concentration by highperformance liquid chromatography (HPLC). HPLC analysis was performed on a Waters Alliance reversed-phase HPLC system (e2695 and 2489; Waters, Milford, USA) with a COSMOSIL 5C18-MS-II column (5 μm, 150 mm × 4.6 mm, Nacalai Tesque, Inc.) and a mobile phase consisting of acetonitrile and 0.1% phosphoric acid (50/50, v/v) in isocratic flow (flow rate of 1.0 mL/min); a monitoring wavelength of 260 nm was chosen based on


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the UV–Vis spectrum. The injection volume was 10 μL, and the column temperature was 40 °C.

RESULTS AND DISCUSSION

Determination of Critical Micelle Concentration. The cmc values of Stevia-G, CnTAC, and Stevia-G/CnTAC were determined by measuring the intensity ratio I1/I3 of the pyrene fluorescence emission. I1 and I3 refer to the emission intensities of pyrene at 373 and 384 nm, respectively. The plots of I1/I3 versus the concentration Log of Stevia-G, CnTAC, and Stevia-G/CnTAC are shown in Figure 1. The pyrene polarity changed, causing a decrease in the value of I1/I3 upon the formation of micelles. The cmc values were chosen from Figure 1 as the concentration of Stevia-G, CnTAC, and SteviaG/CnTAC at which there is a sharp decrease in the value of I1/I3. The analytical method suggested by Aguair et al.

24

was used for determining the cmc from the I1/I3 data. I1/I3

data were fitted to the sigmoid type equation of the form 𝐼1

𝐴1 - 𝐴2

𝐼3 = 𝐴2 + 1 + 𝑒𝑥𝑝[(𝑐 -

𝑥0)/𝑏]

.

(1)


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In Eq. (1), c represents the surfactant and mixed surfactant concentration, x0 is the value of c corresponding to the center of the sigmoid, A1 and A2 are the upper and lower limits of the sigmoid, respectively, and the term b reflects the range of c where a sudden change in I1/I3 occurs. The cmc values were taken as equal to x0, and these are shown in Figure 1 and Table 1. The values of the cmc at 25 °C in aqueous solutions of C14TAC, C16TAC, C18TAC, and Stevia-G were 4.78, 1.30, 0.573, and 8.0 mM, respectively, and were found to be very close to literature values. 15, 25, 26

Figure 1 Variation of I1/I3 of pyrene with the concentration of transglycosylated stevia (Stevia-G), trimethylammonium chloride (CnTAC) and Stevia-G/CnTAC at different αCnTAC from 0.0 to 1.0.


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Table 1: Various Physicochemical Parameters of the Transglycosylated Stevia (SteviaG)/ Trimethylammonium Chloride (CnTAC) Mixed System Obtained from Fluorescence Measurements and Hydrodynamic Diameter (Dh) from DLS Measurements at 25 °C in Water

αCnTA

cmcid

cmcex

C

(mM)

(mM)

X1 id

X2 id

X1 ex

X2 ex

ƒ1

ƒ2

βm

Dh d.nm

Stevia-G/C14TAC 0.0

10.0

10.0

--

--

--

--

--

--

--

3.3

0.2

8.20

2.58

0.343

0.656

0.452

0.547

0.238

0.376

-

1.7

4.780 0.4

6.95

2.98

0.582

0.417

0.531

0.468

0.469

0.381

-

1.4

3.443 0.6

6.04

2.19

0.758

0.241

0.588

0.412

0.467

0.212

-

1.2

4.479 0.8

5.33

2.65

0.893

0.106

0.676

0.324

0.656

0.163

-

1.1

4.014 1.0

4.78

4.78

--

--

--

--

--

--

--

1.0

Stevia-G/C16TAC 0.0

10.0

10.0

--

--

--

--

--

--

--

3.3

0.2

4.28

0.98

0.657

0.342

0.541

0.459

0.278

0.170

-

1.9

6.064 0.4

2.72

0.69

0.836

0.163

0.598

0.402

0.355

0.102

-

1.6

6.407 0.6

1.99

0.65

0.920

0.079

0.648

0.352

0.462

0.073

-

1.3

6.215 0.8

1.57

1.17

0.968

0.031

0.809

0.190

0.889

0.122

-

1.2

3.228 1.0

1.30

1.30

--

--

--

--

--

--

--

1.1

--

--

--

--

3.3

Stevia-G/C18TAC 0.0

10.0

10.0

--

--

--


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0.2

2.33

0.47

0.813

0.186

0.581

0.419

0.282

0.089

-

2.3

7.203 0.4

1.32

0.36

0.920

0.079

0.636

0.364

0.395

0.059

-

1.9

7.007 0.6

0.92

0.32

0.963

0.036

0.680

0.319

0.492

0.040

-

1.4

6.963 0.8

0.71

0.31

0.985

0.014

0.729

0.270

0.593

0.023

-

1.3

7.113 1.0

0.57

0.57

--

--

--

--

--

--

--

1.2

In Table 1, the effect of chain length on the formation of micelles and mixed micelles can be seen. The cmc values for all of the mixed systems (Stevia-G/CnTAC) are in the middle of the two single-component cmc values, indicating that the micellization of Stevia-G was favored in the presence of CnTAC. The lowering of the cmc values of the mixed systems was caused by the enhanced hydrophobic interactions between Stevia-G and the CnTAC molecules. The cmc values for the Stevia-G/C18TAC mixed systems were lower than those for the mixed system of Stevia-G/C14TAC and Stevia-G/C16TAC at all mole fractions because of the longer carbon chain length of the C18 surfactant. The stronger hydrophobic interaction among the alkyl tails of the longer carbon chain surfactants enhances the tendency to form micelles. 27


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Thermodynamic Interaction Parameter of Mixed Micelle. Clint's phase separation model was used to study the nature of the interactions between Stevia-G and the CnTAC surfactants.

28

The cmc values of Stevia-G/CnTAC (cmc*) were determined from the

relationship between cmc* and the cmc values of Stevia-G (cmc1) and CnTAC (cmc2) as represented in Eq. (2): 1 𝑐𝑚𝑐 *

=

𝛼1 𝑐𝑚𝑐1

+

(1 - 𝛼1 ) 𝑐𝑚𝑐2

.

(2)

α was the molar fraction of Stevia-G/CnTAC, and cmc* was the cmc of the mixed system when it behaves ideally according to Clint's equation.

28

The cmc* values of the mixed

system calculated from Clint's equation were termed as the ideal cmc values, and these were shown in Table 1 and Figure 2 (1 to 3). The experimental cmc values were much lower than the ideal values, indicating the formation of mixed micelle between Stevia-G and CnTAC in aqueous media. Figure 2 (1), the cmc values of Stevia-G/C14TAC were decreased from C14TAC 0.4 to 0.2 because of the lower mole fraction C14TAC was increase the electrostatic self repulsion and favored to chain-chain interaction into the mixed micelle. But when mole


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fraction was higher C14TAC 0.4 the the electrostatic self repulsion of C14TAC reduced, which caused increased the cmc values than C14TAC 0.2. C16TAC and C18TAC have long chain length and cmc values were increased from αCnTAC 0.4 to 0.2. It might be at higher mole fraction of Stevia-G favored to self solubilized into the mixed micelle and favored to chain-chain interaction which enhanced the hydrophobic interaction between Stevia-G and C16TAC/ C18TAC shown in Figure 2 (2) and Table 1.

Figure 2 The cmc values of the transglycosylated stevia (Stevia-G)/trimethylammonium chloride (CnTAC) mixed systems: (1) C14TAC, (2) C16TAC, and (3) C18TAC, obtained from fluorescence probe methods at a range of mole fractions of CnTAC in bulk solution in water. The ideal cmc values (solid red line) were calculated using Clint's equation.


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The estimate of synergism of the experimental cmc values from the ideal cmc* value, and hence the nonideality of the mixed systems were made using Rubingh's equation 29: 𝛼 𝑐𝑚𝑐 𝑋1𝑐𝑚𝑐1 ) 𝑋21ln ( 1 𝛼 )𝑐𝑚𝑐 (1 - 𝑋1)2ln[ (1 - 1 (1 - 𝑋1)𝑐𝑚𝑐1]

= 1.

(3)

By the regular solution theory, cmc was the critical micelle concentration of the mixed systems, and X1 was the mole fraction of αCnTAC in the mixed micelle. The micellar mole fraction of the drug in the ideal state (Xid) was calculated using Motomura's approximation, 30 shown in Eq. (4): 𝑋𝑖𝑑 =

[

(𝛼1𝑐𝑚𝑐2)

]

(𝛼1𝑐𝑚𝑐2 + (1 - 𝛼1)𝑐𝑚𝑐1)

.

(4)

Figures 3, 4, and 5 illustrate the comparison of X1 (Rubingh) with Xid (Motomura) as a function of αCnTAC. From Figure 3 (A), the micellar composition for Stevia-G/C14TAC, as calculated from Eq. (3), and the crossover of the plots of XStevia-G,id and XC14TAC,id versus

C14TAC were taken at C14TAC = 0.33 such that XC14TAC,id > XStevia-G,id in the range 0.33 ≤ C14TAC< 1 and XC14TAC,id < XStevia-G,id in the range 0 < C14TAC < 0.33. It was interested to observe that the crossover of XC14TAC,ex and XStevia-G,ex versus the C14TAC plots also took


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place at Stevia-G = 0.33. This was true for all of the mixed systems because, when X1 =

X2 = 0.5 (the crossover point), Eqs. (3) and (4) merge to give the same result such that, at the crossover point, 1 was equal to c01/(c01 + c02). 31 In the case of the mixed system of Stevia-G/C16TAC and Stevia-G-C18TAC, it was clear that the mixed micelles consisted of a higher mole ratio of C16TAC and C18TAC than Stevia-G. The crossover points of XC16TAC,ex or XC18TAC,ex and XStevia-G,ex versus C16TAC or

C18TAC could not be observed. Eq. (3) was used to obtain the values of X1 (Table 1), which was used to calculate the interaction parameter, βm, using Eq. (5): ln⁡

𝛽𝑚 =

(

𝑐𝑚𝑐 ∝ 1 𝑐𝑚𝑐1𝑋1

(1 - 𝑋1)2

)

.

(5)

Eq. (5) was an indication of the degree of interaction between two surfactants in mixed micelles and accounts for any deviation from ideality. Increase of the electrostatic self repulsion cause chain-chain interaction was more favorable with increased mole fraction for C18TAC > C16TAC> C14TAC which leads to hydrophobic interaction caused more negative −βm (average βm= −4.17 for C14TAC, −5.47 for C16TAC, and −7.07 for C18TAC),


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as shown in Figure (3C, 4C & 5C) and Table 1. The more negative −βm and lower cmc values increased the interactions within the mixed system and could be due to a decrease in the ionic headgroup repulsions caused by the presence of Stevia-G between the CnTAC headgroup. However, the values of βm were different in all Stevia-G/CnTAC mixtures was found to be not constant with varying of α CnTAC, shown in Figure 3 (C), 4(C) and 5 (C). It might be errors in the cmc which was affected by the βm values with composition with a large difference. The non-constancy of βm with mixture composition was shown the shortcomings of Rubingh's approach for binary mixtures.32 The negative βm values have commonly been ascribed to the interaction between the head groups leading to electrostatic stabilization or compatibility of the surfactant species and thus represent a measure of the synergistic behavior between surfactants. 33 βm could be affected by nonconsideration effects like counterions binding, vary chain length, vary ionic strength. According to Rubingh’s approach, the βm should be constant over the entire range of mixed composition. In this work, we could not find constant βm values referred to


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composition-dependent likely earlier reported for anionic-nonionic, anionic-cationic, anionic-anionic, cationic-cationic, and nonionic-nonionic surfactant systems.34-38 On the other hand, headgroup/headgroup and chain/chain interactions reported by Maeda

39

and Ruiz et al.

Maeda

39

reported that different chain lengths of surfactants used in a mixed system

40

may also be present in the Stevia-G/CnTAC mixed system.

increase the possibility of chain/chain interactions, but the βm values are explained by headgroup/headgroup interactions. Maeda presented another parameter B1 to represent the chain/chain interaction, which contributed to the stability of the mixed micelles. A function of the ionic surfactant in the mixed micelle (Xm) was used to determine the free energy of micellization (ΔGmic) from Eq. (6):

ΔGmic= RT(B0 + B1 Xm + B2 Xm2),

(6)

where B0 = ln cmc2 (cmc2 for the nonionic surfactant), B1 + B2 = ln(cmc1/cmc2) (cmc1 for the ionic surfactant), and B2 = −βm. The values of B0, B1, B2, and ΔGmic were shown in Table 2. From Eq. (6), ΔGmic expressed a measure of the stability of the mixed micelles, and B1 represents the standard free energy change associated with the introduction of the CnTAC component


21


Page 22 of 54

into a Stevia-G micelle paired with the released of one Stevia-G component from the micelle. The negative values of ΔGmic (average for CnTAC from 0.2 to 0.8) were SteviaG/C14TAC = −13.23, Stevia-G/C16TAC = −16.63, and Stevia-G/C18TAC = −18.49 kJmol−1 for the mixed Stevia-G-CnTAC systems. The contribution of B1 played an important role in changing the cmc values of the Stevia-G micelles when the CnTAC component entered the Stevia-G micelle. A similar observation was made in a cationic–nonionic mixture by Dar et al.

41

The negative B1 values indicate that the chain–chain interactions contribute

to mixed micelle formation in the Stevia-G/CnTAC mixed system, as shown in Table 2. As the CnTAC mole fraction increased, the βm values decreased, which caused a reduction in the electrostatic self-repulsion between the CnTAC headgroups because of the presence of Stevia-G. A possible reason is that a minimum amount of CnTAC was transferred from the micellar phase during mixed micelle formation.


22

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Table 2 Thermodynamic Parameters of the Micellization of Transglycosylated Stevia (Stevia-G)/ Trimethylammonium Chloride (CnTAC) Mixed System in Aqueous Solution Obtained from ITC Measurements at 25 °C αCnTAC

B0

B1

B2

∆Gmic

∆Goexe

∆Gomic

ΔHmic

ΔSmic

kjmol-1

kjmol-1

PS

kjmol-1

J mol-1 K-1

Maeda

kjmol-1

Stevia-G/C14TAC 0.0

-

-

-

-

-

-21.36

1.046

75.19

-

-

4.780

-13.23

-2.929

-24.71

-0.117

82.55

13.23

5.519

-

-

3.443

-13.23

-2.114

-24.36

-0.121

81.34

13.23

4.181

-

-

4.479

-13.23

-2.688

-25.12

-0.133

83.86

13.23

5.217

-

-

4.014

-13.23

-2.159

-24.65

-0.154

82.20

13.23

4.752

-

-

-

-

-

-23.19

-0.087

77.52

13.23 0.2 0.4 0.6 0.8 1.0

13.23 Stevia-G/C16TAC 0.0

-

-

-

-

-

-21.36

1.046

75.19

-

-

6.064

-16.65

-3.722

-27.11

-0.622

88.91

16.46

8.104

-

-

6.407

-16.68

-3.798

-27.98

-1.313

89.50

16.46

8.448

-

-

6.215

-16.69

-3.508

-28.13

-1.700

88.70

16.46

8.255

-

-

3.228

-16.65

-1.224

-26.67

-2.175

82.22

16.46

5.268

16.46 0.2 0.4 0.6 0.8


23


1.0

-

-

-

-

-

Page 24 of 54

-26.41

-1.761

82.73

16.46 Stevia-G/C18TAC 0.0

-

-

-

-

-

-21.36

1.046

75.19

-

-

7.203

-26.95

-4.323

-28.93

-1.504

92.05

18.49

10.06

-

-

7.007

-27.01

-4.010

-29.59

-1.532

94.18

18.49

9.867

-

-

6.963

-27.06

-3.738

-29.89

-3.723

87.81

18.49

9.822

-

-

7.113

-27.14

-3.476

-29.96

-5.254

82.93

18.49

9.972

-

-

-

-

-

-28.44

-4.481

80.42

18.49 0.2 0.4 0.6 0.8 1.0

18.49

The attractive interaction between Stevia-G and CnTAC, the nonideality in the mixed micelle, could be expressed regarding the molar excess standard free energy of micellization, Gex. 42 Eq. (7) was used to determine Gex:

Gex = RT [x1lnf1 + x2lnf2].

(7)

Eq. (7) could be written in terms of the interaction parameter

Gex = RT x1 x2m.

(8)


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The Gex value (the average for CnTAC from 0.2 to 0.8) for Stevia-G with C14TAC was −2.47, that for Stevia-G with C16TAC was −3.06, and that for Stevia-G with C18TAC was −3.88, as found from Eq. (8), shown in Table 2. Figure 3, 4, 5 (D), the higher negative values of Gex suggested that stable mixed micelles were formed in the Stevia-G and CnTAC systems when Stevia-G in high mole fraction. The other parameters that suggested the non-ideal behavior of the mixed systems are the activity coefficients (ƒ1, ƒ2) 29, which were evaluated using Eqs. (9) and (10): ƒ1 = 𝑒𝑥𝑝[𝛽.(1 ― 𝑋1)2 ]

(9)

ƒ2 = 𝑒𝑥𝑝[𝛽.(𝑋 1)2 ] .

(10)

The activity coefficients (ƒ1, ƒ2) were less than unity for all of the mixed Stevia-G and CnTAC systems, which indicates non-ideal behavior, as shown in Figures 3, 4, and 5 and Table 1.


25


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Figure 3 (A) Experimental values of micellar composition (X1) and ideal micellar composition (X1id), (B) activity coefficients (ƒ1, ƒ2), and (C) interaction parameter (βm) and (D) excess free energy (∆Gex) of mixed micellization for transglycosylated stevia (SteviaG)/ trimethylammonium chloride (C14TAC) mixtures in an aqueous medium at 25 °C.


26

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Gibbs Free Energies, Enthalpies, and Entropies of Micellization. It has been stated that the direct measurement of ΔHmic by ITC is the preferred method for obtaining the thermodynamic properties of micelle formation.

43

Briefly, ΔHmic was evaluated by

measuring the heat changes that occur when small quantities of a concentrated single or


28

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mixed surfactant solution were titrated into distilled water. The enthalpy of micellization

ΔHmic was obtained by subtracting the observed initial average enthalpy of the nonmicellar region from the final average enthalpy of the micellar region44–46, as shown in Figure 6. The change in Gibbs free energy of micellization (ΔGmic) could then be derived using different models. In the pseudo-phase separation model, the micellar part was treated as a separate phase, and the values of ΔGmic were calculated from the cmc data using the following equation 47:

ΔGmic = RT lnXcmc,

(11)

where Xcmc was the critical micelle concentration defined as a mole fraction, T was the absolute temperature, and R was the gas constant. The Gibbs equation could determine the entropy ΔSmic:

ΔSmic = (ΔHmic – ΔGmic)/T.

(12)

Typical data were obtained from ITC experiments performed with CnTAC, SteviaG, and Stevia-G/CnTAC solutions at a concentration of 100 mM in water at a fixed temperature of 25°C, as shown in Figure 6 (A, B, and C) and Table 2.


29


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Figure 6 Isothermal titration calorimetry (ITC) curves for titrating (A) transglycosylated stevia (Stevia-G)/trimethylammonium chloride (C14TAC), (B) Stevia-G/C16TAC and (C) Stevia-G/C18TAC into water at 25 °C. The enthalpy of dilution of Stevia-G and CnTAC in water at 25 °C. (D) Enthalpy, (E) free energy, and (F) entropy of micellization plotted against the overall mole fraction of CnTAC.


30

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The micellization process of the pure CnTAC became spontaneous, and the entropy change became more positive with increasing alkyl chain length. In the present study, the ΔHmic values for C14TAC, C16TAC, C18TAC, and Stevia-G were determined as −0.87, −1.76, −4.81, and 1.046 kJmol−1, respectively. The absolute values of ΔHmic strongly depended on the nature of the headgroup. In this system, CnTAC has the same type of headgroup but different chain lengths. Therefore, ΔHmic was decreased in the order C18TAC < C16TAC < C14TAC < Stevia-G. The enthalpies for CnTAC were exothermic, but for Stevia-G, it was endothermic. For CnTAC, the values of ΔHmic and

ΔGmic were all negative, and the values of ΔSmic were positive, which is due to some disruptions of the water structure during micellization. These results indicate that micellization was driven by entropy and enthalpy simultaneously. However, for Stevia-G, the values of both ΔHmic and ΔSmic were positive, which shows that the micellization was only driven by entropy. 48, 49 For the Stevia-G and CnTAC mixtures, ΔHmic increased with the mole fraction αCnTAC from 0.2–0.8, as shown in Figure 6(D) and Table 2. The reason for the increase in

ΔHmic was that CnTAC was dissolved in the Stevia-G mixed micelles continuously, ACS Paragon Plus Environment

31


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allowing the formation of CnTAC-rich mixed micelles. A similar observation was reported by Zheng et al. for a TX-100/DTAB mixed micelle. 50 Moreover, ΔHmic also increased with increasing chain length in the Stevia-G and CnTAC system because of the stronger hydrophobic interaction between CnTAC and Stevia-G with the increased number of carbon atoms. However, the entropies of micellization, ΔSmic, were positive for all of the Stevia-G/CnTAC systems, indicating the formation of a stable mixed micelle of SteviaG/CnTAC, as shown in Figure 6(F) and Table 2. It was thought that, during the formation of the Stevia-G/CnTAC mixed micelles, the structure of the water molecules around the hydrocarbon chains was destroyed when the hydrocarbon chains are eliminated from the aqueous medium to form the interior of the mixed micelles. With the increasing CnTAC chain length, the changes in ΔHmic and ΔSmic have the same effects on ΔGmic. The ΔGmic was becomes more negative with an increase in the number of carbon atoms of CnTAC in the mixed system, as shown in Figure 6(E) and Table 2. Therefore, mixed micelle formation became more spontaneous than single micelle formation with longer carbon chains in the surfactant.


32

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Size Measurements. To characterize the hydrodynamic diameter (Dh) of the Stevia-G, CnTAC and Stevia-G/CnTAC mixtures (C*(αStevia-G + αCnTAC)), samples of αStevia-

G

at 1.0, 0.8, 0.6, 0.4, 0.2 and 0.0 at 50 mM (C) concentration was measured by DLS, as

shown in Figure 7 and Table 1. The Dh of pure Stevia-G, C14TAC, C16TAC and C18TAC was 3.3, 1.0, 1.1, 1.2 nm repectivily. The size of Stevia-G and C14TAC was almost close to reported values.14, 51 The Dh values of the CnTAC was slightly increased with increasing carbon number of the alkyl chain, which indicates that the rigid and hydrophobic chains lead to aggregate formation. From Table 1 and Figure 7, the Dh values indicated the formation of Stevia-G/CnTAC mixed micelle was very small in size from αStevia-G 0.8-0.2. The observed results indicated that the effect on Stevia-G with increasing of αStevia-G 0.80.2 caused the decrease aggregate size (Table 1), which was due to close distance between Stevia-G and CnTAC.12 The size also decreases due to intercalation of charged head groups of CnTAC in the non-ionic Stevia-G aggregate which increases the repulsive interactions of charged mixed micelles.52


33


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Figure 7 Change of the hydrodynamic diameter (Dh) for C14TAC, C16TAC and C18TAC with varying of αStevia-G 1.0 to 0.0 at 25 °C. The concentration of the Stevia-G/CnTAC solutions was 50 mM.

Solubility Test. When considering drug solubility, it is necessary to consider not only the interaction between Stevia-G and CnTAC but also the interaction between the resultant mixed micelle and the target drug. The solubility test was conducted using rebamipide, a poorly water-soluble drug, to clarify the effect of each molar fraction on drug solubility. The solubility of rebamipide in water has been reported as 0.0435 μM.

53

The solubilization capability of the Stevia-G/CnTAC mixed system for rebamipide was


34

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evaluated using the micelle-water partition coefficient (Km). The solubility of rebamipide at each additive concentration was plotted as a function of the total surfactant concentration for each mole fraction in each data set, as shown in Figure 8.

Figure 8 Variation of the solubility of rebamipide in (A) pure surfactant and the (B) transglycosylated stevia (Stevia-G)/trimethylammonium chloride (C14TAC), (C) SteviaG/C16TAC, and (D) Stevia-G/C18TAC mixed micellar phases as a function of the concentration of the micellized surfactant.


35


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The apparent solubility of rebamipide rose linearly and was enhanced by the increased concentration of the surfactant above the cmc. The MSR quantified the solubilization capacities of different surfactant systems for rebamipide above the cmc. 52, 54, 55

MSR was determined by Eq. (13):

MSR = [St] – [Scmc]/Ct – cmc,

(13)

where St was the apparent solubility of rebamipide at a particular surfactant concentration greater than the cmc, Ct was the total molar concentration of the surfactant at which S was evaluated, and Scmc was the apparent solubility of the drug at the cmc. The plot of

St–Scmc versus Ct–cmc was shown in Figure 9(A–D), and the slope of this linear plot, which gave the value of MSR, was calculated using least-squares linear regression. The micelle-water partition coefficient, Km,

56

was a measure of the effectiveness of

solubilization, and it was determined by Eq. 14:

Km = MSR/Scmc･Vm･(1 + MSR).

(14)

Vm was the molar volume of water equal to 0.01805 L/mol at 25°C. The calculated values of MSR and logKm were shown in Figure 9(E & F) and Table 3.


36

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Figure 9 Plots of (St–Scmc) of rebamipide against the surfactant concentration in micellar form (Ct–cmc) of (A) single surfactant and the mixed systems of (B) (SteviaG)/trimethylammonium chloride (C14TAC), (C) Stevia-G/C16TAC, and (D) SteviaG/C18TAC. Comparison of the molar solubilization ratio (MSR) and LogKm of rebamipide as a function of the mole fraction of αCnTAC for the different mixed surfactant systems as shown in (E) and (F), respectively.


37


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From Figure 9(E) and Table 3, the MSR value was seen to increase with the mole fraction of CnTAC in Stevia-G/CnTAC. When the MSR and Km values were compared between the different carbon chain length systems, the highest value was observed for the Stevia-G/C16TAC system at a mole fraction αCnTAC from 0.2 ≤ 0.6, as shown in Figure 9(F) and Table 3. On the other hand, at a mole fraction of αCnTAC from 0.6 ≤ 0.8, the MSR and Km values increased with carbon chain length. Two possible reasons for this behavior are inferred: (1) rebamipide was solubilized at the stern layer of the Stevia-G/CnTAC mixed micelle and caused a larger reduction in the Km for C18TAC than C16TAC at a mole fraction αCnTAC between 0.2 ≤ 0.6, and (2) the solubilization of rebamipide into the micelle was obstructed by the steric hindrance between Stevia-G and rebamipide. The steric hindrance reduced with increasing mole fraction αCnTAC, and CnTAC itself was solubilized in the Stevia-G micelle to change the micelle environment, thereby enhancing rebamipide solubility. These results suggest that, although the more stable mixed micelle was formed from the longest carbon chain length of CnTAC, the mixed micelle with C16TAC showed the highest solubilization capacity.


38

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Table 3 Values of the Molar Solubilization Ratio (MSR) and LogKm of Single and Mixed Transglycosylated Stevia (Stevia-G)/ Trimethylammonium Chloride (CnTAC) Surfactants in Aqueous Solution

αCnTAC

MSR

Km˟105

LogKm

Stevia-G/C14TAC 0.0

0.0066

0.0390

3.59

0.2

0.0106

0.1696

4.22

0.4

0.0139

0.3106

4.49

0.6

0.0193

0.8371

4.92

0.8

0.0243

1.1953

5.07

1.0

0.0310

1.4507

5.16

Stevia-G/C16TAC 0.0

0.0066

0.0390

3.59

0.2

0.0109

1.2246

5.08

0.4

0.0143

2.3783

5.37

0.6

0.0236

6.1562

5.78

0.8

0.0506

3.6058

5.55

1.0

0.0759

10.574

6.02

Stevia-G/C18TAC 0.0

0.0066

0.0390

3.59

0.2

0.0067

0.2185

4.34

0.4

0.0121

0.6802

4.83

0.6

0.0262

2.2166

5.34

0.8

0.0555

8.8276

5.94

1.0

0.0819

8.9302

5.95

CONCLUSION


39


Page 40 of 54

The influence of the length of the side chain of the CnTAC surfactant on the formation of a mixed micelle with Stevia-G was examined by fluorometric and ITC experiments. Rubingh's and Maeda's theories were applied to evaluate this mixed surfactant system, and both approaches suggested that there are attractive interactions between the constituent surfactants in the mixed micelle. Moreover, despite the difference in chain length, the mixed Stevia-G/CnTAC components underwent a synergistic interaction in the mixed micelles. DLS experiments evaluated the very small size of the micelle, and mixed micelle was formed.

ΔHmic, ΔSmic, and ΔGmic were used to evaluate the micellization of the mixed Stevia-G/CnTAC system. ΔHmic increased with an increase in ΔSmic, revealing the compensation of enthalpy and entropy. The values of ΔHmic and ΔSmic increased with increasing mole fraction αCnTAC, and the compensation between ΔHmic and ΔSmic resulted in a negative ΔGmic for the mixed micelles of all compositions, indicating that the interaction between Stevia-G and CnTAC enhanced the stability of the mixed micelles. The mixed micelle of Stevia-G and CnTAC showed greatly improved apparent solubility of rebamipide in the aqueous medium. The solubility of the single surfactants


40

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was compared, and increasing chain length indicated increased values of MSR and Km. Stevia-G showed the minimum solubility for rebamipide. Interestingly, for the mixed micelles from Stevia-G/CnTAC, the MSR increased with αCnTAC from 0.0 to 1.0. The Stevia-G/C18TAC system had a low LogKm of 4.99 (average from αCnTAC 0–1.0) as compared with Stevia-G/C16TAC (LogKm of 5.24) because of the steric hindrance between Stevia-G and rebamipide. Rebamipide might be solubilized into the hydrophobic part of the mixed micelles, thereby causing a higher MSR and Km for Stevia-G/C16TAC. These studies greatly contribute to the future development of mixed micelles for the formulation of poorly water-soluble drugs using Stevia-G and ionic surfactants.

Notes The authors declare no competing financial interest.

Acknowledgements


41


Page 42 of 54

This research was supported by grants from JSPS KAKENHI (grant number 18K06614; Tokyo, Japan) and a Grant in Aid from the Hosokawa Powder Technology Foundation.

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Investigation of Physiological Properties of Transglycosylated Stevia

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