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Cyclodextrins and Surfactants in Aqueous Solution above CMC: Where are the Cyclodextrins Located? Marina Tsianou, and Ankitkumar I. Fajalia Langmuir, Just Accepted Manuscript • DOI: 10.1021/la5013999 • Publication Date (Web): 15 Aug 2014 Downloaded from http://pubs.acs.org on August 16, 2014

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Cyclodextrins and Surfactants in Aqueous Solution above CMC: Where are the Cyclodextrins Located? Marina Tsianou* and Ankitkumar I. Fajalia Department of Chemical & Biological Engineering, University at Buffalo, The State University of New York (SUNY), Buffalo, New York 14260-4200, USA

Abstract Cyclodextrins (CDs) are known to bind surfactant molecules below the surfactant critical micelle concentration (CMC), however interactions of CDs with surfactant micelles (above the CMC) are not well understood. In particular, direct structural evidence of the location of CDs in the different subphases found in micellar solutions is lacking. We have utilized small angle neutron scattering (SANS) with contrast matching to probe the localization of α-cyclodextrin (α-CD) and hydroxypropyl βcyclodextrin (HPβ-CD) in sodium dodecyl sulfate (SDS) micelles in aqueous (D2O) solutions. SANS data from solutions containing either hydrogenated or deuterated surfactants were analyzed considering three different scenaria pertaining to the localization of cyclodextrin, either all in solution, or in the micelle shell, or in the micelle core, and were simultaneously fitted using the core-shell prolate ellipsoid form factor and Hansen-Hayter-based structure factor. The scenario that considered a fraction of CD to localize in the micelle core described well SANS data from both hydrogenated- and deuterated-SDS - CD - D2O solutions, while the other two scenaria did not. Among the various structural and interaction parameters obtained from this analysis, it emerged that the micelle core consisted of up to ~10% HPβ-CD or ~16% α-CD with respect to the total number of molecules (surfactants and CDs) present in the micelle at 25 mM SDS, and up to 14% HPβ-CD or 28% α-CD at 50 mM SDS. This is the first study that provides direct evidence on the location of cyclodextrin in the core of surfactant micelles. An improved understanding of CD interactions with surfactants and lipids would enable better strategies for drug encapsulation and delivery with CDs.

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1. Introduction Surfactant molecules are well-known to self-assemble in aqueous solutions into micelles above a certain concentration denoted as critical micelle concentration (CMC).1 The design of a number of industrial formulations relies on the solution behavior of surfactants2-7, which can be affected profoundly by the presence of various solutes.8-10 In particular, supramolecules such as cyclodextrins (CDs) may alter the surfactant micellization in water because of host-guest type interactions with the hydrophobic part of the surfactant.11-21 CDs are composed of α-D-glucopyranoside units that form a ring (Figure S1). Native cyclodextrins and their derivatives find a number of applications in pharmaceutical, cosmetic, and food industries for encapsulation of hydrophobic or volatile actives, in analytical chemistry, and in catalysis.21-27

The exterior of CDs is hydrophilic, while the central cavity presents a hydrophobic

environment which drives its binding with the hydrocarbon tails of surfactants or lipids to form inclusion complexes.25-26 The inclusion complexation of α-cyclodextrin (6-member glucose ring), β-cyclodextrin (7-member glucose ring) or γ-cyclodextrin (8-member glucose ring) with common surfactants has been examined using various techniques.11, 13, 16, 18-19 High values of the reported binding constants indicate high stability of the CD-surfactant complexes in aqueous solutions. The binding affinity of cyclodextrins with surfactant molecules and the CD-surfactant stoichiometric ratios at surfactant concentration lower than the CMC has been addressed,11,

13-20, 28

however, very few studies have considered CD-surfactant interactions at conditions where micelles form.11,

15, 29-33

CDs can bind with surfactant molecules and thus shift the equilibrium between

unmicellized surfactants, increase the CMC,11 and finally destroy the micelles.31 Still, the structure of surfactant micelles that form in the presence of CDs is not established. Different opinions exist in the literature regarding the location of CDs in micellar solutions. Speed of sound measurements on sodium dodecyl sulfate (SDS) micelles formed in the presence of β-CD concluded that the micelles are unaffected by the presence of CD-SDS complexes in the solution, and that neither CD nor CD-SDS complexes participate in the micelles.32 Nevertheless, the authors warned that “stronger experimental evidence is

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needed”.32 Static florescence quenching measurements found similar micelle aggregation numbers either in the absence or in the presence of different types of cyclodextrins (α-CD, β-CD, hydroxypropyl β-CD, maltosyl-β-CD, and γ-CD) in SDS aqueous solution.31 On the other hand, another study reported the formation of mixed β-CD-SDS micelles below the CMC, and suggested the incorporation of CDs inside the micelles.34

Rheological measurements in aqueous solutions of SDS associated with oppositely

charged polyelectrolyte suggested the localization of CD-SDS complexes in the micelles that form crosslinks between the polyelectrolyte chains.21 In addition to the controversy regarding CD partitioning between micelles and solution phase, the structure of micelles in the presence of CDs is still unknown. Adsorption of ring-shaped molecules such as crown ethers (1,4,7,10,13,16-hexaoxacyclooctadecan, 2,5,8,11,14,17-hexaoxabicyclo[16.4.0]dicosane) on the SDS micelle surface has been reported.35-37 A recent investigation suggested the adsorption of unsubstituted and methylated cyclodextrins on sodium decanoate micelles, indicating that methylated cyclodextrins localize in the micelle shell.37 To date, no direct structural evidence exists that can reveal the localization of CDs in micelles. Several key questions remain open: How do cyclodextrins interact with surfactant micelles? Do CDs affect the micelle structure, and if yes, by what mechanism? Do CDs remain near the surface of micelles in the “palisade layer” or participate in the micelle core? Do the cavity size and functionalization of cyclodextrin affect its partitioning and localization? Answers to these questions can emerge from small angle neutron scattering (SANS) that probes directly the nanostructure that may be present in CD-surfactant solutions. Moreover, SANS can provide structural information on a portion of an overall structure by selectively deuterating the remaining part of the structure so as to match its scattering to that of the deuterated solvent. SANS has been used widely to characterize the structure of surfactant micelles in solution and the interactions between them.38-40 In the present study, we answer the open question about CD localization in micellar solutions by investigating interactions between sodium dodecyl sulfate (SDS) micelles and α-cyclodextrin (α-CD) or

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hydroxypropyl β-cyclodextrin (HPβ-CD) using SANS with contrast variation. In view of the controversy regarding the location of CDs, we analyze the scattering data from surfactant solutions in the presence of CDs considering three different scenaria that involve the localization of CDs either in the solution, or in the micelle shell, or in the micelle core. We obtain quantitative data on the micelle structure and intermicelle interactions using appropriate form factor and structure factor. To the best of our knowledge, this report provides the first direct evidence on cyclodextrin localization in surfactant micelles.

2. Materials and Methods 2.1 Sample preparation Hydrogenous sodium dodecyl sulfate (SDS) was purchased from Sigma and deuterated sodium dodecyl sulfate (d-SDS) from Cambridge Isotope Laboratories, Tewksbury, MA. Heavy water (D2O) was purchased from Cambridge Isotope Laboratories. α-cyclodextrin and hydroxypropyl β-cyclodextrin were purchased from Aldrich. Because β-CD is sparingly soluble in water, hydroxypropyl β-CD has been used in the present study due to its higher aqueous solubility. The degree of substitution of hydroxypropyl groups for β-cyclodextrin was specified as 4.3 by the supplier. All chemicals were used as received. Stock solutions of surfactant and of CD in D2O were first prepared, and then mixed in appropriate ratios with each other and with D2O to obtain the desire final concentration.

Adequate time for

equilibration was allowed. Combinations of CCD and CSDS were chosen such that some micelles would be present in the samples so that the different CD localization scenarios can be evaluated.

SDS

concentrations were 25 mM or 50 mM in aqueous solutions. Concentrations of α-CD were kept at 10 and 20 mM in aqueous solutions having SDS concentration of 25 mM, and at 20 and 40 mM at 50 mM SDS, in order to maintain similar CD to SDS ratios. Similarly, the concentrations of HP-β-CD were set at 5 and 10 mM in aqueous solutions at 25 mM SDS, and at 10 and 20 mM for 50 mM SDS solutions.

2.2 Small angle neutron scattering (SANS)

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Details on SANS data collection and reduction and SANS data fits and analysis in terms of appropriate form and structure factors are presented in “Supporting Information”. In what follows we highlight some points that are directly relevant to the “Results and Discussion” section. Sodium dodecyl sulfate is known to form nearly monodispersed, spherical or ellipsoidal micelles in aqueous solutions at low surfactant concentrations.39-41 The micelle can be described by a core encompassing the hydrocarbon tails of the surfactants, surrounded by a shell containing surfactant head groups, counter ions and some associated water molecules with average scattering length density which is rather different compared to that of the micelle core or of the bulk solvent.38-40 Accordingly, we have utilized a core-shell monodispersed prolate ellipsoid to describe the structure of the SDS micelles (Figure 1). The structure factor S ( q ) that we used is based on Hansen-Hayter’s rescaled mean spherical approximation (RMSA) framework, in which micelles are approximated as charge spheres of diameter

σ 0 interacting through ionimpenetrable dimensionless screened Coulomb potential.35, 38, 41-47 Equations and parameters for the form factor P ( q ) and for S ( q ) are given in “Supporting Information”. A protocol suggested by Sheu et al.39, 41 and Caponetti et al.35-36 has been adopted, with some modifications, in the present study for fitting the form and structure factors to the SANS intensity profiles.

Major fitting parameters are the surfactant aggregation number η (number of surfactant

molecules per micelle) and the total charge on a micelle Z. Two additional parameters have been introduced to describe the distribution of CDs in the system: the fraction of CDs forming 1:1 complexes,

λ (which accounts for the distribution of CD molecules in the solution among 1:1 or 2:1 inclusion complexes), and the fraction of CDs participating in micelles, Γ. Two types of cyclodextrin molecules have been considered in this study: (1) α-CD which forms both 1:1 and 2:1 complexes with the surfactant (SDS) molecules19, 48 and (2) HPβ-CD which forms mostly 1:1 complexes with the surfactant.19 We calculated λ as follows.

2.3 Calculation of λ values based on SDS-α-CD multiple equilibria

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CDs form inclusion complexes with SDS molecules in aqueous solutions.11, 13, 15, 17, 19, 31-32, 48-50 While the values of the reported equilibrium constants vary to a great extent, the relative ratio of the constants for multiple equilibria of CD-SDS complexation suggest that 1:1 inclusion complexes are dominant for the HPβ-CD and SDS system. However, for α-CD and SDS, along with 1:1 complexes, 2:1 complexes are also present in a considerable amount.19, 49-51 We consider here the multiple equilibria between uncomplexed α-CD, uncomplexed SDS, and 1:1 and 2:1 CD-SDS complexes as shown in equations (1) and (2).19, 49-50 With the equilibrium constants K1 and K2 reported in the literature for the CD-SDS binding, we calculate the equilibrium concentrations of the CD, SDS and complexes by solving the nonlinear equations for the multiple equilibria.14, 28 Using these equilibrium concentrations, we then calculate the λ value that we subsequently used during the fitting of the SANS intensity data. K1

SDS + CD ⇔ SDS − CD

(1)

K2

SDS − CD + CD ⇔ SDS − CD2 K1 =

K2 =

CS −CDeq C eq ⋅ CCDeq CS −CD2 eq

CS −CDeq ⋅ CCDeq

(2)

(3)

(4)

CCDi = CCDeq + CS −CDeq + 2CS −CD2 eq

(5)

Ci = Ceq + CS −CDeq + CS −CD2 eq

(6)

The values of the equilibrium constants K1 and K2, as represented in equations (3) and (4), used in the present study for the mixture of SDS and α-CD in aqueous solutions are 21000 M-1 and 18000 M-1, respectively (obtained using ion selective electromotive force measurement by Yunus et al19). Mole balances for CD and for SDS are shown in equations (5) and (6), where CCDi and C i are the total

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concentrations of CD and surfactant, respectively. Rearranging equations (3) and (4) one can obtain expressions for the equilibrium concentrations of 1:1 and 2:1 complexes: CS −CDeq = K1 ⋅ C eq ⋅ CCDeq and

CS −CD2 eq = K1 K 2 ⋅ C eq ⋅ CCDeq 2 . After substituting CS −CDeq and CS −CD2 eq in equations (5) and (6) by these expressions and rearranging we obtain equation (7).

C eq =

Ci

(7)

2

1 + K1CCDeq + K1 K 2 CCDeq

The substitution of equation (7) in equation (5) followed by rearrangement gives the cubic equation (8) to solve for the CD concentration at equilibrium, CCDeq . 3

2

K1 K 2 CCDeq + ( K1 + 2 K1 K 2C i − K1 K 2CCDi ) CCDeq + (1 + K1C i − K1CCDi )CCDeq − CCDi = 0

CCDeq has been obtained by solving equation (8) numerically.

(8)

The concentration of surfactant at

equilibrium C eq has been obtained from equation (7). The concentrations of 1:1 complex CS −CDeq and 2:1 complex CS −CD2 eq at equilibrium have been calculated using equations (9) and (10) that are derived from the mole balance equations of CD and SDS.

CS −CDeq = 2(C i − C eq ) − (CCDi − CCDeq )

(9)

CS −CD2 eq = (CCDi − CCDeq ) − (Ci − C eq )

(10)

The equilibrium concentration of the uncomplexed α-CD, CCDeq , was calculated as mentioned above. The concentration of uncomplexed CDs at equilibrium was found negligible compared to the initial concentration of the CDs when the total concentration ratio ( CCDi : C i ) is less than approximately 2. Thus, for the calculation of λ the concentration of uncomplexed CD is set to zero. By definition, λ is related to the equilibrium concentrations of complexes by the following equations:

CS −CDeq = λCCDi

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(11)

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CS −CD2 eq =

(1 − λ )CCDi 2

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(12)

Rearrangement of equations (11) and (12) gives the following equation for the calculation of λ.

λ=

CS −CDeq 2CS −CD2 eq + CS −CDeq

(13)

Table 1 presents the equilibrium concentrations for various species and the λ values calculated for the concentrations of SDS and α-CD relevant to this study. These values of λ are used for the fitting of small angle neutron scattering intensity data analysis in the case of α-CD. For the mixture of SDS and β-CD in aqueous solutions, the reported19 values of equilibrium constants K1 and K2 are 21000 M-1 and 210 M-1, respectively. As the value of K 2 is very small compared to K1 for βCD, the equilibrium concentration of 2:1 complexes was found using the above calculations to be 1.29 x 10-4 M, which is negligible compared to the 1:1 concentration of 0.0197 M. Consequently, for the SDS-HPβ-CD-D2O system the value of λ was fixed at 1.

2.4 Contrast variation technique revealing CD localization Since the scattering lengths of the hydrogen atoms are very different from those of deuterium atoms, by selectively deuterating a part of the structure, one can match out the scattering length densities of that part with that of the deuterated solvent in order to generate contrast because of the undeuterated portion of the structure. We have used deuterated surfactant hydrocarbon tails to match out the scattering intensity due to SDS molecules with the solvent D2O while keeping the cyclodextrins hydrogenated. Since the contrast between the deuterated surfactant micelles and the deuterated water is negligible, hydrogenated CDs, if localized at inter-micelle distances, would produce measurable scattering contrast and would thus increase the scattering emanating from the solution. In order to obtain direct structural evidence of CD localization in micelle, we have described the scattering data obtained from contrast-matched d-SDS solutions by using the same core-shell prolate

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ellipsoid form factor and Hansen-Hayter-based structure factor that we used in the case of hydrogenated surfactants. SANS data of both hydrogenated and deuterated-SDS systems were simultaneously fitted using the same set of fitting parameters (η , Z, Γ, λ) and the same fitting procedure. Although SANS has been applied for hydrogenated surfactants in the presence of other macrocyclic compounds such as crown ethers35-36, to our best knowledge contrast matching by using deuterated SDS and hydrogenated macrocycle to confirm the localization of a macrocycle has not been reported in the literature.

3. Results and Discussion 3.1 SDS micelles in D2O We establish the structure of SDS micelles in the absence of CD but at surfactant concentrations relevant to the SDS+CD study. Scattering profiles for 8.9, 25, and 50 mM SDS in D2O are shown in Figure 2. At 8.9 mM SDS, near the CMC, the scattering is low since there are very few micelles. The overall scattering intensity increases with increasing surfactant concentration, and interacting objects (evidently micelles) are present at 25 and 50 mM SDS, as signified by the correlation peaks. In order to obtain micelle structure and inter-micelle interactions in the absence of CDs, the SANS data were fitted using the form and structure factors described in the previous section. The values of the parameters obtained here are in agreement with literature.36, effective diameter σ

0

41, 47

Micelles are larger (larger

and thicker shell δ ), more elongated, and comprise of more surfactant molecules

at 50 mM SDS compared to 25 mM SDS (Table S2 in Supporting Information). The surfactant packing density in a micelle is higher for 50 mM SDS compared to 25 mM SDS as indicated by the smaller surface area per surfactant molecule (92 Å2) at 50 mM SDS. The interaction peak in the scattering profile becomes more pronounced with increasing surfactant concentration, indicating increasing order in the solution, and shifts towards higher q values, indicating smaller inter-micelle distances d in 50 mM SDS

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solutions (Table S3).37 The micelle volume fraction and number density both increase at higher SDS concentrations; also the charge on a micelle and the electrostatic coupling between micelles. The presence of CDs is expected to affect the micelle structure as well as inter-micelle interactions, depending on where the CD molecules are located with respect to the micelles.

3.2 Different scenaria considered for location of cyclodextrins in SDS solutions In order to determine the location of CDs between the solution and micellar domains, we analyzed the SANS data considering three different scenaria in the form and structure factor: 1. CDs remain in solution as CD-SDS complexes and do not associate with micelles. In this scenario, the micelles consist of only surfactant and all the CD molecules stay in the solution in the form of 1:1 or 2:1 CD-SDS complexes. Static fluorescence quenching31 and speed of sound measurements32 studies on CD-surfactant binding have suggested this scenario as the most appropriate to describe the CD location. For this scenario, the fraction of cyclodextrins in the micelle was fixed at Γ = 0 when fitting the SANS data. 2. A fraction of CDs adsorb on the micelle surface while the remainder CDs are in the solution. Here we hypothesize that a fraction of CDs adsorb on the micelle surface and localize in the shell (“palisade layer”) of the micelle, while the remainder CDs are in solution free or as CD-SDS complexes. Macrocyclic compounds and methylated cyclodextrins have been reported to localize in the micelle shell, in support of this scenario.35-37 The fraction of CDs in the micelle, Γ, was considered as a fitting parameter here. The calculations of the scattering length densities, volumes and micelle dimensions took into account the CD localization in the micelle shell. 3. A fraction of CD-SDS complexes form mixed micelles with the surfactant. We consider a fraction of CDs to localize in the micelle core in the form of CD-SDS complexes, while the rest of CDs are in solution also as CD-SDS complexes. Reports21, 34 on the formation of mixed β-CD-SDS micelles support this scenario. The fraction of CDs partitioning in the micelle, Γ, was varied

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during the SANS data fittings, and the amount of CDs localized per micelle was thus determined. Parameters such as hydration numbers, λ, and dielectric constant were kept the same as for scenario 1.

HPβ-CD - SDS - D2O β-CDs can form inclusion complexes with the hydrocarbon tails of the surfactant and are thus able to shift the equilibrium of surfactants between the micelle pseudo-phase and the solution more towards the solution. Because of their larger ring (7 glucose units) compared to α-CD (6 glucose units), β-CD molecules form primarily 1:1 CD:SDS inclusion complexes.19 Scattering intensity profiles of hydrogenated SDS in D2O in the presence of various amounts of HP-β-CD are shown in Figure 3.

The CD concentrations have been selected to maintain similar

CCD / CSDS ratios in both 25 and 50 mM SDS. At a given SDS concentration, addition of HPβ-CD gradually decreases the scattering peak intensities and broadens the peaks, indicating a decrease in the micelle aggregation number and charge. The peak position qmax shifts slightly towards higher q values, indicating a decrease in inter-micelle distance and an increase in the micelle number density. When the surfactant concentration is fixed, the increase in the micelle number densities suggests a decrease in the aggregation number. We have used deuterated surfactants to match out their scattering contrast with the solvent (D2O). Hence any scattering observed from deuterated surfactants in D2O in the presence of hydrogenated CDs is mainly due to the scattering contrast of CDs, which would provide direct evidence of CD localization. Figure 4 shows SANS data for HPβ-CD in 25 and 50 mM deuterated-SDS solutions. Since scattering by deuterated-SDS in D2O is very low and with no features (Figure 2) due to insignificant scattering contrast between surfactant and solvent, the peak observed in Figure 4 clearly confirms the organization of CDs in the solution at length-scales similar to inter-micelle distances. Further, the scattering intensities in the presence of deuterated surfactants are higher than the scattering intensity of hydrogenated HPβ-CD - D2O solutions in the absence of surfactants (at same CD concentration 10 mM) (Figure 4). Addition of HPβ-

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CD to the deuterated SDS - D2O solution results in an increase in the scattering intensity which is opposite to the trend observed for hydrogenated-SDS - D2O solutions. It worth noting that the location of the interaction peak maximum in the deuterated-SDS - HPβCD - D2O case matches exactly that observed in the hydrogenated SDS - HPβ-CD - D2O system, which indicates the same inter-micelle distances. In particular, for both deuterated and hydrogenous 25 mM SDS with 5 mM HPβ-CD, the correlation peak is at q ~ 0.048 Å-1, while with 10 mM HPβ-CD the peak is at q ~ 0.056 Å-1. Similarly, 50 mM solutions of either deuterated or hydrogenated SDS exhibit peaks at the same q values (q = 0.058 with 10 mM HPβ-CD and q = 0.064 with 20 mM HPβ-CD). The correlation peak maxima shift at higher q indicates smaller inter-micelle distances with higher CD concentration. SANS data from both hydrogenated-SDS and deuterated-SDS D2O solutions in the presence of HPβ-CD were simultaneously fitted such that the same set of extracted parameters can adequately describe the scattering from both types of systems. Fits to the SANS data using the core-shell prolate ellipsoid form factor and Hansen-Hayter-based structure factor equations obtained considering scenario 3 are shown by solid lines in Figure 3 and Figure 4, for hydrogenated and deuterated SDS, respectively. In this case we allowed CD to localize in the micelle core and treated Γ as a fitting parameter. It is evident from the figures that the model and extracted parameters obtained under scenario 3 (reported in Table 2) capture the scattering data reasonably well over the entire q range, in support of the localization of a fraction of HPβ-CD in the micelle core. Moreover, the fits using scenario 3 are far better (and the parameters physically realistic) than fits under scenaria 1 and 2. Fits under scenario 3 have R2 values greater than 0.998, and maximum root mean square (RMS) error of 0.00124. The RMS error under scenario 3 is ~6 and ~27 times smaller compared to the RMS error in scenario 1 and 2, respectively. Fits to data from hydrogenated-SDS - HPβ-CD - D2O solutions considering scenario 1, where

Γ = 0 , are unable to capture well the peaks and the low q region (see solid lines in Figure S2), with correlation coefficient less than 0.921. Moreover, the corresponding fits to the SANS data of deuterated SDS+CD solutions were poor (results not reported here). SANS data of D2O solutions containing

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hydrogeneous SDS were also fitted (see solid lines in Figure S3) considering a fraction of CD to be adsorbed in the micelle shell as per scenario 2. Compared to scenario 1, these fits are able to capture the data well (correlation coefficient 0.988), however, it proved impossible to simultaneously fit the SANS data with a set of parameter which can describe the scattering from both hydrogenated and deuterated surfactant solutions. Figure S4 shows SANS data from aqueous (D2O) HPβ-CD solutions containing deuterated-SDS and the calculated SANS intensity profiles using the same parameters used for fitting the SANS data from SDS-CD-D2O solutions containing hydrogeneous SDS (shown in Figure S3). The calculated profiles do not capture the SANS data (in particular, the calculated intensity exhibits multiple peaks which are not present in the experimental data), providing clear indication that scenario 2 is not physically appropriate to describe the location of HPβ-CDs in the micelles.

α-CD - SDS - D2O Scattering profiles of hydrogenated-SDS in D2O at various α-CD concentrations are shown in Figure 5. An increase in α-CD concentration at a fixed surfactant concentration results in a decrease in the peak intensities and a broadening of the peaks, trends similar to what is observed for SDS in D2O when the surfactant concentration decreases (Figure 2). The decrease in scattering intensities with increasing CD concentrations indicates a reduction in micelle dimensions and interactions associated with a drop in the aggregation number and charge. Figure 6 shows scattering profiles from deuterated-SDS D2O solutions in the presence of hydrogenated α-CDs at 25 and 50 mM surfactant. Unlike the case of hydrogenated surfactant (Figure 5), addition of hydrogenated α-CDs in the deuterated surfactant solutions results in an increase in the scattering intensity (albeit at an overall low level). Further, the scattering intensities from hydrogenated CDs in D2O in the presence of deuterated SDS are higher than the corresponding scattering from hydrogenated CD in D2O in the absence of deuterated surfactants. Since scattering from deuterated-SDS

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in D2O is negligible (Figure 2), the rise in the scattering intensity of hydrogenated α-CD solutions in the presence of deuterated surfactants indicates the direct effect of micelle-mediated localization of α-CDs. To confirm the localization of α-CDs in micelles per scenario 3, we have fitted SANS data from both hydrogenated-SDS and deuterated-SDS D2O solutions in the presence of α-CD such that the same set of extracted parameters (reported in Table 3) can describe the scattering from both hydrogenated and deuterated surfactant systems. The corresponding fits to the data are shown with solid lines in Figure 5 and Figure 6, for hydrogenated and deuterated surfactant systems, respectively. It is evident that scenario 3 consistently captures the scattering well over the entire q range for all the hydrogenated surfactant solutions investigated here. Further, the extracted parameters for micelle structure and inter-micelle interactions have physically realistic values as shown in Table 3. For the deuterated surfactant solutions, having relatively low intensity, the form and structure factors used fit the data reasonably well in the intermediate q range. Unlike scenario 2 (discussed in the next paragraph), the fitted profiles do not exhibit multiple peaks in the form factors in the given q range. Data at low q values were not captured well, likely because of low signal to noise ratios. Moreover, α-CD has lower solubility in water than HPβ-CD and is prone to aggregation (as discussed in “Supporting Information”, a cylinder form factor, representing molecular tube-like structure, fits the SANS well in the low q region ( 0.02 < q < 007 Å-1)).

Notwithstanding possible α-CD aggregation in solution, the present data support scenario 3, and together with the conclusions for HPβ-CD, provide strong evidence of α-CD localization inside the SDS micelles. SANS data fits were also attempted considering the other two scenaria for CD location. The fits with scenario 1 where Γ=0 are poor for all α-CD - h-SDS - D2O samples (Figure S5) and unable to capture the peaks and the low q region. Figure S6 (solid lines) shows fits to SANS data from α-CD D2O solutions containing hydrogenated SDS considering scenario 2. While these fits are able to capture the data well (correlation coefficient 0.995 and RMS error 0.12), calculated SANS intensity profiles using the same structural parameters but for systems containing deuterated SDS do not capture the SANS data

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(solid lines in Figure S7). In particular, the calculated intensity profiles have multiple peaks which are not present in the experimental data, clearly suggesting that scenario 2 cannot capture the α-CD location.

3.3 SDS micelles in the presence of CDs: CD location affects micelle structure HPβ-CD - SDS - D2O Table 2 shows the extracted parameters describing micelle composition and structure for the best fit scenario (scenario 3) that considers a fraction of cyclodextrins to localize in the micelle core. The amount of CDs on the micelle core is quantified by the number of cyclodextrin molecules in a micelle k and the fraction of cyclodextrins entering the micelles Γ . For 25 mM SDS D2O solution, addition of 10 mM HPβ-CD results in the formation of mixed micelles each having on the average 3 CD and 33 surfactant molecules. For 50 mM SDS and 20 mM HPβ-CD in D2O, each micelle contains ~5 CD and 32 SDS molecules. The fraction of cyclodextrin present in the micelles increases to 19% of the overall cyclodextrin concentration with the addition of 10 mM HPβ-CD in 25 mM surfactant solution. Similarly, around 30% of the total 20 mM HPβ-CD enter the micelle core in the case of 50 mM SDS solutions. Localization of cyclodextrins in the micelles affects the micelle structure profoundly.

As

indicated above, the majority of the CDs remain in solution complexing higher amount of surfactants as evident from the higher effective CMC values reported in Table 2. Similar CMC increase in the presence of different CDs has been reported by Al-Sherbini.29 The aggregation number decreases drastically for both 25 and 50 mM surfactant solutions upon HPβ-CD addition (Table 2) due to higher amount of surfactant complexed in solution as well as lower packing density of surfactant in micelles due to CD localization in the micelle core. The surface area per surfactant molecule increases rapidly, indicating a decrease in the packing density of the surfactants in the micelle (see Table 2). The micelle size also decreases upon CD addition, and the micelle shape changes progressively from prolate ellipsoid to sphere. The localization of CDs in the micelle core also affects inter-micelle interactions. Addition of HPβ-CD leads to a decrease in the micelle charge by ~36% upon 10 mM HPβ-CD addition to 25 mM

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SDS, and by ~50% upon 20 mM HPβ-CD addition to 50 mM SDS. This reduction in the micelle charge can be explained by a decrease in the number of surfactant headgroups in the micelle shell despite the increase in surfactant counterion dissociation in the shell. The micelle charge reduction is associated with decreased surface potential on the micelle and electrostatic coupling Γk between micelles (Table 2). Further, HPβ-CD addition increases the micelle number density, increases the ionic strength of the solution, decreases the Debye length κ −1 , and reduces the inter-micelle distances (Table 2).

α-CD - SDS - D2O Table 3 reports parameters describing α-CD effects on micelle structure and interactions obtained by the best fit scenario (scenario 3). Upon addition of α-CD in 25mM SDS solutions, the amount of cyclodextrins entering the micelle core increases up to 12% of the total CD concentration of 20 mM. At the higher surfactant concentration of 50 mM, 27% of the total CD concentration of 40 mM reside in the micelles. Addition of 20 mM α-CD to 25 mM SDS solution results in the localization of ~ 9 CDs with ~47 surfactants per micelle. At 40 mM α-CD in 50 mM SDS approximately 15 CD molecules and 40 surfactant molecules are in a micelle. As in the case of HPβ-CD, addition of α-CD affects the micelle structure: the surfactant aggregation number decreases (Table 3) but at a lower slope of decrease with respect to α-CD concentration compared to HPβ-CD. The micelle size also decreases, and the micelle shape (reflected in the axis ratio ε ) changes from prolate ellipsoid to sphere with α-CD addition (Table 3). The surface area per surfactant molecule increases upon α-CD addition. As observed upon addition of HPβ-CD, localization of α-CD in the micelle core results in a decrease in the total charge on a micelle, the surface potential and the electrostatic coupling constant, and a longer Debye length κ −1 (Table 3). Specifically, the coupling constant decrease per 1 mM of α-CD is around 0.012 for 25 mM and 0.007 for 50 mM SDS solution.

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Compared to HPβ-CD, the percentage of α-CD localized in the micelle per unit increase in total CD concentration is lower, which indicates a weaker ability of α-CD to influence the micelles. The lower effectiveness of α-CD compared to HPβ-CD can be mainly attributed to the difference in the preferred complex ratios between CDs and SDS. Since α-CD forms both 1:1 and 2:1 CD-SDS complexes, α-CD can bind with 2/(λ+1) times lower amount of surfactant compared to HPβ-CD. For instance, for 50 mM SDS and 20 mM CD aqueous solutions, λ= 0.62 for α-CD (Table 1) which indicates that HPβ-CD could bind with 2/(λ+1) = 1.23 times more surfactant compared to α-CD, and thus should appear 23% more effective. In our study, the observed slope of decrease in aggregation number with respect to CD concentration is ~0.9 for α-CD and ~2.1 for HPβ-CD at 20 mM CD. The slope for HPβ-CD is ~1.33 times higher than that for α-CD indicating a 33% higher effectiveness for HPβ-CD, which is higher than the 23% expected from λ. Such higher observed effectiveness can be explained in terms of the different ability of CDs to encapsulate surfactant hydrophobic tails. α-CD can tightly fit 4 carbon atoms of a fully stretched alkyl chain, and 3 carbon atoms for a tail with 1 kink in the conformation. However, β-CD can encapsulate 4 carbon atoms of an all-trans alkyl chain and 8 carbon atoms for a tail with 2 kinks in the conformation.19, 48 Hence 1:1 complexes of α-CD should affect the micelle structure to a lesser extent compared to HPβ-CD upon localization in the micelle. Andrade-Dias et al.37 have examined the effects of unsubstituted or methylated cyclodextrins on sodium decanoate micelles in terms of changes in the micelle surface-to-volume (S/V) ratios, determined by fitting the Porod equation at high q, and the inter-micelle distances d, obtained from the location of the correlation peak. They found a linear increase in the S/V ratio with increasing CD concentration for methylated CDs, but no change upon addition of unsubstituted CDs.

On the basis of the higher

[∆(S/V)/∆CCD] slope for methylated CDs compared to unsubstituted CDs, they have suggested the localization of methylated CDs (but not unsubstituted CDs) near the micelle shell. They have proposed that methylated CDs do not form inclusion complexes with the surfactant due to geometric restrictions, but rather adsorb on the micelle surface due to favorable dielectric properties at the micelle shell

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compared to water. They have also assumed that the micelle aggregation number is not affected by the presence of methylated CDs, and have utilized the value of aggregation number derived from SANS data from surfactants in the absence of CDs. Although they have alluded to a decrease in the aggregation number from the trends in inter-micelle distances for unsubstituted CDs, they have not reported values for aggregation numbers. Further, S/V ratios were approximated utilizing only the high q portion of the scattering data (for the Porod fit), while the micelle number densities were estimated from the intermicelle distances assuming cubic arrangement of micelles in the solution. Since their assessment on CD location was based on the S/V ratios and estimated number densities, possible errors in these parameters could produce corresponding errors in their results. For example, when we used a similar approach to estimate aggregation numbers from SDS micelle number densities, we found significantly lower aggregation number values than those obtained from SANS fits to appropriate form and structure factors. While these authors have described their SANS data in a rather qualitative manner, the quantitative analysis presented here provides a better assessment on CD location and effects on the micelles. Such data and analysis presented in our study have not been reported elsewhere.

4. Conclusions The self-assembly of surfactants in aqueous solutions can be affected profoundly by the presence of cyclodextrins.11-20 The binding of cyclodextrins with surfactant molecules at concentrations lower than the CMC has been well-studied11, 13-20, 28, however, the binding of CDs with surfactant at concentrations above the CMC and the effects of CDs on the micelles have not been explored well. Key questions remain open: Do CDs affect the micelle structure? By which mechanism? Does the cyclodextrin type affect its partitioning and localization? The present study addresses CD localization in micellar solutions, and CD effects on micelle structure and interactions. We investigate interactions of sodium dodecyl sulfate (SDS) micelles in aqueous (D2O) solutions with two different types of CDs, α-cyclodextrin (α-CD) or hydroxypropyl β-

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cyclodextrin (HPβ-CD), using small angle neutron scattering (SANS). We have analyzed SANS data using the core-shell prolate ellipsoid form factor and the Hansen-Hayter structure factor considering three scenaria pertaining to cyclodextrin localization: (1) CDs stay in solution in the form of 1:1 or 2:1 CDSDS complexes away from the micelles, (2) a fraction of CDs adsorb on the micelle shell, while the remainder CD is in solution, and (3) a fraction of CD-SDS complexes participate in the formation of mixed micelles resulting in localization of CD in the micelle core, with the remainder CD is in solution. In order to obtain direct structural evidence of CD localization and establish the best among the three scenaria considered, we have employed SANS with contrast variation where we used deuterated surfactants while keeping the CDs hydrogenated. The higher intensities and correlation peaks (especially for HPβ-CD) observed in deuterated SDS D2O solutions in the presence of CDs (compared to a flat profile in the case of d-SDS solutions in D2O) intimate the localization of CDs at length-scales corresponding to the inter-micelle distances. Unlike scenario 1 and 2, the form and structure factors considering scenario 3, i.e., localization of CDs in the micelle core, were able to simultaneously fit SANS data for both hydrogenated and deuterated SDS D2O solutions in the presence of CDs. Moreover, fits under scenario 3 are consistently better compared to the fits considering scenario 1 or scenario 2, in further support of CD localization in the micelle core. Details about CD effects on the SDS micelle composition and structure and inter-micelle interactions emerge from SANS data fits to the best scenario. For example, for 25 mM SDS-D2O solution, addition of 10 mM HPβ-CD resulted in mixed micelles consisting of ~ 3 CD and ~33 surfactant molecules, while addition of 20 mM α-CD resulted in ~ 9 CDs and ~47 surfactants per micelle. The number of CDs localized per micelle upon addition of HPβ-CD and α-CD was ~66% and ~55% higher, respectively, for 50 mM SDS solutions compared to 25 mM. The localization of CDs in micelles directly affects the micelle shape, from ellipsoids to spheres, and structure, resulting in ~6% decrease in surfactant aggregation number for HPβCD compared to ~2% decrease for α-CD per 1 mM CD increase. Along with the micelle structure, CD addition affects inter-micelle interactions as reflected, e.g., in decreasing

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the electrostatic coupling constant by ~3.3% and the micelle surface potential by ~2.6% per 1 mM of HPβ-CD added, and attributed to a decrease in the number of headgroups in the shell. Overall, HPβ-CD is more effective than α-CD in influencing micelle structure and interactions, something we attribute to a difference in the preferred complex ratios between CDs and SDS and the smaller size of 1:1 α-CD-SDS complexes. α-CD can bind with 2/(λ+1) times less surfactant compared to a similar amount of HPβ-CD because the former can form both 1:1 and 2:1 CD-SDS complexes while the latter forms primarily 1:1 CD-SDS complexes. To our best knowledge, this is the first report on CD localization in SDS using SANS, and only the second SANS contrast variation report on CD localization in surfactant micelles. Our study reveals the interaction of CDs with SDS micelles and provides direct evidence of CD location in the micelle core. An improved understanding of CD localization in micelles would enable the design of better strategies for micelle-templated nanoparticle synthesis or for site-specific drug31 or gene27 delivery using drug-CD complexes. For example, CD-drug complexes can be used to deliver drugs in cells through the cell membrane which consists of phospholipids (surfactants).

CDs will form complexes with the

phospholipids and release the encapsulated drug in the cell provided that the binding affinity of CD with lipids is higher than that with the drug. The tendency of CD-surfactant complexes to incorporate into micelles, and by extrapolation into lipid membranes, can further assist targeted drug delivery into cells.

Acknowledgements We acknowledge the support of the National Institute of Standards and Technology (NIST), Gaithersburg, MD, in providing the neutron research facilities used in this work. We also thank Prof. P. Alexandridis (Chemical & Biological Engineering, SUNY-Buffalo) for helpful discussions.

Supporting Information is available free of charge via the Internet at http://pubs.acs.org

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Table 1. Concentrations of uncomplexed SDS, uncomplexed α-CD, and 1:1 and 2:1 CD-SDS complexes, and fraction of 1:1 complexes present in the aqueous solutions at equilibrium. CSDSi is the total surfactant concentration, CCDi is the total cyclodextrin concentration, λ is the fraction of 1:1 type complexes, CSDSeq is the equilibrium concentration of uncomplexed SDS, and CCDeq is the equilibrium concentration of uncomplexed cyclodextrin. CS-CDeq is the equilibrium concentration of 1:1 CD-SDS complexes, CS-CD2eq is the equilibrium concentration of 2:1 CD:SDS complexes, and Γmax is the maximum possible fraction of CD molecules going in the micelles (using a CMC value of 8 mM for SDS in aqueous solution).

CSDSi (mM) CCDi (mM)

λ

CSDSeq (mM)

CCDeq (mM)

CS-CDeq (mM)

CS-CD2eq (mM)

Γmax

25

10

0.616

16.93

0.017

6.15

1.91

0.010

25

20

0.425

10.77

0.038

8.49

5.74

0.439

50

20

0.616

33.85

0.017

12.31

3.84

0.505

50

40

0.425

21.52

0.038

16.98

11.49

0.719

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

Table 2. Parameters describing the micelle structure and interactions that have been obtained by fitting SANS data of SDS in D2O in the presence of HPβ-CD at different concentrations using the form and structure factors described in the text: η is the aggregation number (number of surfactant molecules per micelle), Z is the charge on a micelle, N P is the number density of micelles, a is the minor core axis,

ε is the ratio of major to minor core axis of a micelle, δ is the shell thickness, σ 0 is the equivalent spherical diameter of the micelle, Smicelle is the surface area of a micelle, and Ssurfactant is the surface area per surfactant head group in a micelle. ρ1, ρ2 and ρS are the scattering length density of core, shell, and solvent, respectively, φ is the micelle volume fraction, k is the number of CD molecules participating in a micelle, λ is the fraction of 1:1 CD:SDS complexes (λ=1 for HPβ-CD-SDS), Γ is the fraction of total CDs participating in micelles, and CCMCeff is the effective critical micellization concentration of the surfactant. d is the inter-micelle distance, Γk is the electrostatic coupling constant for the micelles, κ-1 is the Debye length of the solvent, and ψ is the electrostatic surface potential on the micelles. Values of uncertainties in the fitting parameters are shown in parentheses in italics.

CSDS+ CHPβ-CD (mM) 25+0 25+5 25+10 50+0 50+10 50+20 CSDS+ CHPβ-CD (mM) 25+0 25+5 25+10 50+0 50+10 50+20

η

Z

NP (Å-3)

a (Å)

ε

δ (Å)

σ0 (Å)

Smicelle (Å-2)

Ssurfactant (Å-2)

CCMCeff (mM)

χ*

72.5 (±0.2) 60.5 (±0.1) 32.9 (±0.2) 80.1 (±0.1) 59.1 (±0.1) 32.4 (±0.0)

9.6 (±0.1) 8.0 (±0.1) 6.1 (±0.1) 13.3 (±0.1) 9.1 (±0.0) 6.6 (±0.0)

1.40E-07 1.69E-07 3.10E-07 3.14E-07 4.28E-07 6.70E-07

21.8 18.2 16.7 24.0 22.9 19.7

1.30 1.09 1.00 1.44 1.37 1.18

4.8 5.2 3.3 4.9 4.5 2.9

46.1 44.6 39.9 47.6 46.1 41.1

6798.1 6286.4 5001.0 7334.6 6835.3 5357.3

93.8 103.8 152.1 91.6 115.7 165.4

8.0 8.0 8.1 8.0 8.0 14.0

4.42 3.96 1.70 6.72 4.33 3.49

ρ1 (Å-2)

ρ2 (Å-2)

ρS (Å-2)

φ

k

Γ

-3.90E-07 -3.90E-07 2.37E-07 -3.90E-07 -4.40E-08 3.84E-07

6.14E-06 6.16E-06 6.17E-06 6.14E-06 6.17E-06 6.17E-06

6.34E-06 6.35E-06 6.35E-06 6.34E-06 6.35E-06 6.36E-06

7.17E-03 7.88E-03 1.03E-02 1.77E-02 2.20E-02 2.44E-02

0.0 0.0 3.7 0.0 2.8 5.4

0.00 0.00 (±0.000) 0.19 (±0.002) 0.00 0.20 (±0.000) 0.30 (±0.000)

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d (Å) 192.6 180.8 147.8 147.1 132.6 114.3

κ-1 (Å)

Γk

91.0 90.5 76.4 51.6 53.3 48.6

0.42 0.36 0.28 0.47 0.38 0.28

ψ (mV) 61.0 53. 0 44.9 70.2 50.8 38.1

Langmuir

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Page 26 of 30

Table 3. Parameters describing the micelle structure and interactions that have been obtained by fitting SANS data of SDS in D2O in the presence of α-CD at different concentrations using the form and structure factors described in the text. The various symbols are defined in the caption of Table 2. N 1 ∑ [( yi − yim ) /σ i ]2 where yi is the ( N − N p + 1) i =1

Reduced χ values52 were calculated using χ =

experimental data point, yim is the model predictions, σ i is the standard deviation of the measurement,

N is the number of data points, and N P is the number of fitting parameters.

CSDS+ Cα-CD (mM)

η

25+0

72.5 (±0.1)

25+10

NP (Å-3)

a (Å)

ε

δ (Å)

σ0 (Å)

Smicelle (Å-2)

Ssurfactant (Å-2)

CCMCeff (mM)

9.6 (±0.1)

1.40E-07

21.8

1.30

4.8

46.1

6798.1

93.8

8.0

4.42

70.6 (±0.2)

6.2 (±0.1)

1.45E-07

21.7

1.30

5.3

47.1

7105.2

100.6

8.0

3.79

25+20

46.5 (±0.2)

5.1 (±0.1)

1.61E-07

23.1

1.39

3.7

44.5

6386.0

137.3

12.6

1.61

50+0

80.1 (±0.1)

13. 3 (±0.1)

3.14E-07

24.0

1.44

4.9

47.6

7334.6

91.6

8.0

6.72

50+20

58.7 (±0.1)

6.3 (±0.0)

3.94E-07

27.7

1.66

4.0

47.5

7472.6

127.4

11.6

2.86

50+40

40.1 (±0.1)

5.3 (±0.0)

4.37E-07

27.2

1.63

2.9

45.1

6699.6

167.3

20.9

3.29

Z

CSDS+ Cα-CD (mM)

ρ1 (Å-2)

ρ2 (Å-2)

ρS (Å-2)

φ

k

λ

25+0

-3.90E-07

6.14E-06

6.34E-06

7.17E-03

0.0

1.00

25+10

-3.53E-07

6.16E-06

6.35E-06

7.94E-03

0.4

25+20

3.25E-07

6.16E-06

6.36E-06

7.45E-03

50+0

-3.90E-07

6.14E-06

6.34E-06

1.77E-02

50+20

2.08E-07

6.16E-06

6.36E-06

2.22E-02

50+40

6.19E-07

6.16E-06

6.37E-06

2.11E-02

χ

d (Å)

κ-1 (Å)

Γk

ψ (mV)

0.00

192.6

91.0

0.42

61.0

0.62

0.01 (±0.002)

190.3

110.9

0.29

40.1

8.8

0.43

0.12 (±0.001)

183.8

115.8

0.24

35.7

0.0

1.00

0.00

147.1

51.6

0.47

70.2

8.6

0.62

0.28 (±0.001)

136.3

66.9

0.30

35.9

14.7

0.43

0.27 (±0.000)

131.7

69.2

0.25

32.6

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b Core

a

-

OSO

3

+

Na

ρs

ρ2

δ

H2O

ρ1

CD

σ0

Figure 1. Prolate core-shell ellipsoid used to model a SDS micelle. The micelle core has a major axis a and a minor axis b, and comprises of hydrophobic alkyl tails of surfactants and cyclodextrins. The micelle shell has thickness δ and consists of surfactant head groups, associated water molecules, and counterions. ρ1 , ρ 2 and ρ s are the scattering length density of core, shell, and solvent, respectively. σ 0

-1

-1

SDS in D2O 8.9 mM

1.0

Intensity I(q) (cm )

is the equivalent spherical diameter of the ellipsoid.

Intensity I(q) (cm )

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

25 mM

0.8

50 mM

0.6

Deu-SDS 50 mM

0.4

10

0

-1

10

-2

10

-3

10

-4

10

2

4

0.01

6 8

2

0.1 -1

q (Å ) 0.2 0.0 0.00

0.05

0.10

0.15

0.20

0.25

0.30

-1

q (Å )

Figure 2. SANS intensity profiles from SDS solutions in D2O at different SDS concentrations (Inset: the same data plotted in logarithmic scale). Also shown are data for 50 mM deuterated SDS in D2O. Markers represent experimental data and solid lines represent fits using the prolate core-shell form factor and Hansen-Hayter structure factor as described in the text.

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Langmuir

-1

CCD = 10 mM

0.6

0.1 0.01 0.001 2

4 6 8

0.01

0.4

Deuterated SDS 25 mM +HPβ-CD+D2O CCD = 5 mM

25

-1

CCD = 5 mM

0.8

30x10

1

Intensity I(q) (cm )

-1

Intensity I(q) (cm )

Intensity I(q) (cm )

-3

SDS 25mM + HPβ-CD+D2O CCD = 0 mM

1.0

2

0.1 -1

q (Å )

CCD = 10 mM

20 15 10 5

0.2

0

0.0

0.00 0.00

0.05

0.10

0.15

0.20

0.25

0.05

0.10

0.15

0.20

0.25

0.30

-1

0.30

q (Å )

-1

q (Å )

-1

CCD = 10 mM

0.8

CCD = 20 mM

0.6

-1

0.1

0.01

0.001 2

4

0.01

0.4

Intensity I(q) (cm )

1.0

30x10

1

Deuterated SDS 50 mM+ HPβ-CD+D2O CCD = 10 mM

-1

SDS 50mM + HPβ-CD+D2O CCD = 0 mM

Intensity I(q) (cm )

-3

Intensity I(q) (cm )

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 28 of 30

6 8

2

-1 0.1

q (Å )

0.2

25

CCD = 20 mM

20

HPβ-CD+D2O CCD = 10 mM

15 10 5 0

0.0

0.00

0.00

0.05

0.10

0.15

0.20

0.25

0.05

0.10

0.30

0.15

0.20

0.25

0.30

-1

q (Å )

-1

q (Å )

Figure 3. SANS intensity profiles from (top) 25 Figure 4. SANS intensity profiles from (top) 25 mM and (bottom) 50 mM hydrogenated-SDS mM and (bottom) 50 mM deuterated-SDS solutions in D2O in the presence of HPβ-CD at solutions in D2O in the presence of HPβ-CD at different

concentrations.

Markers

represent different concentrations.

Markers represent

experimental data and solid lines represent fits using experimental data, and solid lines represent the prolate core-shell form factor and Hansen- intensities calculated using the prolate core-shell Hayter-based structure factor described in the text. form factor and Hansen-Hayter-based structure The data were fitted considering scenario 3, where a factor described in the text for the case of scenario fraction of CDs participate in the micelle core while 3 (a fraction of CDs participate in the micelle the remainder remains in the solution.

core), using the same parameters as for the corresponding systems (shown in Figure 3) consisting of hydrogenated SDS+HPβ-CD+D2O (the various parameters are shown in Table 2).

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30x10

Deuterated-SDS 25 mM +α-CD+D2O CCD = 10 mM

-1

1

CCD = 20 mM

0.6

-1

Intensity I(q) (cm )

-1

Intensity I(q) (cm )

CCD = 10 mM

0.8

Intensity I(q) (cm )

-3

SDS 25mM + α-CD+D2O CCD = 0 mM

1.0

0.1

0.01

0.001 2

4

6 8

0.01

0.4

2

0.1 -1

q (Å )

25

CCD = 20 mM

20 15 10 5

0.2

0

0.0

0.00

0.00

0.05

0.10

0.15

0.20

0.25

0.05

0.10

0.30

0.15

0.20

0.25

0.30

-1

q (Å )

-1

q (Å ) Deuterated SDS 50mM +α-CD+D2O CCD = 20 mM

-1

CCD = 40 mM

0.6

0.1

-1

CCD = 20 mM

0.8

30x10

1

Intensity I(q) (cm )

-1

Intensity I(q) (cm )

-3

SDS 50 mM +α-CD+D2O CCD = 0 mM

1.0

Intensity I(q) (cm )

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

0.01

0.001 2

4

6 8

0.01

0.4

2

0.1 -1

q (Å )

0.2

25

CCD = 40 mM

20

α-CD+D2O CCD = 20 mM

15 10 5 0

0.0

0.00

0.00

0.05

0.10

0.15

0.20

0.25

0.05

0.10

0.30

0.15

0.20

0.25

0.30

-1

q (Å )

-1

q (Å )

Figure 5. S ANS intensity profiles from (top) 25 Figure 6. SANS intensity profiles from (top) 25 mM and (bottom) 50 mM hydrogenated SDS mM and (bottom) 50 mM deuterated-SDS solutions in D2O in the presence of α-CD at different solutions in D2O in the presence of α-CD at concentrations.

Markers represent experimental different concentrations.

Markers represent

data and solid lines represent fits using the prolate experimental data, and solid lines represent core-shell form factor and Hansen-Hayter-based intensities calculated using the prolate core-shell structure factor described in the text. The data were form factor and Hansen-Hayter-based structure fitted considering scenario 3, where a fraction of factor described in the text for the case of scenario CDs participate in the micelle core while the 3 (a fraction of CDs participate in the micelle remainder remains in the solution

core), using the same parameters as for the corresponding systems (shown in Figure 5) consisting of hydrogenated SDS+α-CD+D2O (the various parameters are shown in Table 3).

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Langmuir

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Cyclodextrins and Surfactants in Aqueous Solution above CMC: Where are the Cyclodextrins Located? Marina Tsianou* and Ankitkumar I. Fajalia

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