ADo

Aa

b

a

ARRAA

KCCSMRSDHD

1

ouc[iac(mtaedcr

0d

Colloids and Surfaces A: Physicochem. Eng. Aspects 386 (2011) 54– 64

Contents lists available at ScienceDirect

Colloids and Surfaces A: Physicochemical andEngineering Aspects

journa l h omepa g e: www.elsev ier .com/ locate /co lsur fa

queous block copolymer–surfactant mixtures—Surface tension,LS and viscosity measurements and their utility in solubilizationf hydrophobic drug and its controlled release

.D. Thummara, N.V. Sastrya,∗, G. Vermab, P.A. Hassanb

Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar 388120, Gujarat, IndiaChemistry Division, Bhabha Atomic Research Centre (BARC), Trombay, Mumbai 400085, India

r t i c l e i n f o

rticle history:eceived 5 March 2011eceived in revised form 26 June 2011ccepted 28 June 2011vailable online 2 July 2011

eywords:opolymer micellesopolymer–surfactant systemsurface active properties

a b s t r a c t

The effects of sodium dodecyl sulfate (SDS) and dodecyl trimethylammonium bromide (DTAB) and poly-oxyethylene (10) isooctyl phenyl ether (TX-100) as additives on the association characteristics of anamphiphilic tri-block copolymer P105 (E37P56E37) were monitored by surface tension, dynamic lightscattering and viscosity measurements at 303.15 and 313.15 K in water as well as in 200 mM sodium chlo-ride aqueous solutions. The successive addition of surfactants resulted not only in the increase of criticalmicelle concentration (CMC) of the copolymer and also in CMC/C20 values indicating that the adsorptiontendency of the copolymer–surfactant complexes at water/air interface is more than the association inthe bulk. The experimental CMC data of binary mixtures were analyzed using regular solution theory tocalculate the interaction parameter. The mixtures exhibited synergistic interaction behavior. The appar-

ixed micellesegular solution theoryynergistic behaviorrug solubilizationydrogelrug release

ent hydrodynamic radius of copolymer micelles decreased drastically by the addition of surfactants andthis destabilization effect has been attributed to the shift of copolymer micelle ↔ unimer equilibrium infavor of latter. Dexamethasone, a drug poorly soluble in aqueous media was solubilized into individualcopolymer or copolymer–surfactants solutions followed by their loading onto agar agar hydrogels for itsimmobilization and dispersion. The drug release profiles were established and drug diffusion coefficientswere calculated.

. Introduction

Poly(ethylene oxide)–poly(propylene oxide)–poly(ethylenexide) (EPE) based tri-block copolymers with variation in molec-lar characteristics such as E/P ratio and molar mass are availableommercially under the trade names of pluronics or poloxamers1,2]. The amphiphilic nature of these block copolymers lead tonteresting adsorption features at air/water interface and self-ssociation behavior in water. The aqueous solutions of theseopolymers typically display a critical micellization concentrationCMC) and critical micellization temperature (CMT) in aqueous

edia and the critical features of self association and adsorption ofhese copolymers have been well reviewed [2,3]. The adsorptionnd micelle generating properties of EPE copolymers have beenxploited for technology based applications such as detergency,

ispersion, stabilization, foaming, emulsification, lubrication,ontrolled release of drugs, and product formulations in industriesanging from agriculture to pharmaceuticals [4–7], as templating

∗ Corresponding author. Tel.: +91 2692 226856; fax: +91 2692 236475.E-mail address: nvsastry 17@rediffmail.com (N.V. Sastry).

927-7757/$ – see front matter © 2011 Elsevier B.V. All rights reserved.oi:10.1016/j.colsurfa.2011.06.027

© 2011 Elsevier B.V. All rights reserved.

agents in the preparation of mesoporous metal oxide thin films[8,9] and also for separation of DNA and proteins, etc. [10,11].

In most of these applications, block copolymers and low molarmass surfactants are commonly employed, as the mixture solutionsare expected to possess not only improved colloidal characteristicsbut also help in fine tuning the viscosity of the media. There-fore the ternary block copolymers/anionic or cationic or nonionicsurfactants/water systems either in the presence or absence ofelectrolytes as additives have received considerable attention andsubject of many of the scientific investigations [12]. The natureof the type of species that are formed in copolymer–surfactantmixture solutions is found to be highly dependent on thesurfactant concentration. At very low surfactant concentration,copolymer–surfactant charged complexes are formed and while atmoderate concentrations, these complexes are broken into mixedmicelles of smaller dimension and at higher concentrations, how-ever the micellization of copolymers is suppressed. Therefore it isessential to fix and work out the particular concentration regimes

for a given copolymer–surfactant system to adjudge their maxi-mum performance in a given application. The CMCs for mixturesolutions of F127 (E97P69E97)–nonionic hexaethylene glycol mono-n-dodecyl ether (C12EO6) [13] and –SDS [14] were determined and

A: Ph

tlttaaiPSadsisasseittwas

afidcah

2

2

hB>praapo

2

sTidT±cpi(5sard

A.D. Thummar et al. / Colloids and Surfaces

he data were analyzed using regular solution theory (RST) to calcu-ate the nonideal interaction parameter. It was concluded that bothhe systems showed synergistic behavior, i.e. favorable interac-ion. Similar conclusions were also drawn for L64 (E13P30E13)–SDSnd –C12EO6 mixtures [15]. In search of new mixed systems ofmphiphilic block copolymer–surfactants with synergistic behav-or, we investigated the binary systems of a pluronic copolymer,105 (E37P58E37) and two conventional ionic surfactants namelyDS, or DTAB and also a nonionic Triton X-100 in water as wells in aqueous sodium chloride solutions using surface tension,ynamic light scattering (DLS) and dilute solution viscosity mea-urements. The copolymer P105, was especially selected becauset has equal percentage of E and P units and form well definedpherical micelles with an hydrophobic core consisting of P unitsnd surrounded by a corona of hydrophilic E units. The mea-urements in sodium chloride aqueous solutions were particularlyelected for copolymer–ionic surfactant systems to minimize theffects of charge repulsions between the complexes formed theren. The CMCs of mixed micelles were determined from surfaceension isotherms and while the changes in the structural fea-ures of copolymer micelles upon the addition of the surfactantsere monitored from DLS measurements. RST formulations were

pplied to ascertain the type of mixing and interactions in mixedystems.

As block copolymer micelles have been successfully employeds novel polymer therapeutics for drug delivery [16], we maderst an attempt to solubilize a poorly soluble anti-inflammatoryrug, dexamethasone into either copolymer aqueous solutions oropolymer–surfactant mixture solutions and then prepared agargar based hydrogels. The release profiles of the drug from theydrogel were constructed by simple dilution with distilled water.

. Experimental

.1. Materials

The tri-block copolymer is a pluronic sample, P105 (E37P58E37)as a molar mass of 6500 g mol−1. It was used as received fromASF Corp. Parsippany, NJ, USA as a gift sample. SDS and DTAB of99% purity were purchased from Sigma–Aldrich. TX-100 of >98%urity was purchased from Aldrich. Sodium chloride of analyticaleagent grade was purchased locally. The drug dexamethasone was

gift sample from a local pharmaceutical company and was useds received. The water was triple distilled over KMnO4 from allyrex glass apparatus and the water samples with a conductivityf 1.2 × 10−6 S cm−1 was used in all the experiments.

.2. Methods

The surface tension (with an accuracy of ±0.03 mN m−1) of givenolution was measured using Wilhelmy plate method by a Surfaceensiometer (Dataphysics, Germany, Model DCAT 11). The plat-num Wilhelmy plate was washed with acetone, rinsed with tripleistilled water and flamed until red hot before each measurement.he uncertainty in the temperature during the measurements was0.1 K. Dynamic light scattering (DLS) measurements on aqueous

opolymer solutions in the absence or presence of surfactants wereerformed using a Malvern 4800 Autosizer employing a 7132 dig-

tal correlator. The solutions were passed through 0.2 �m filtersacrodisc) to ensure that they are dust free. Ar ion laser operated a14.5 nm with a maximum power output of 2 W was used as light

ource. Measurements were made over a 50–130◦ angle range. Theverage decay rate was obtained from the electric field autocor-elation function, g1(�), using method of cumulants. The averageecay rate (� ) from the second-order cumulant expansion of the

ysicochem. Eng. Aspects 386 (2011) 54– 64 55

electric field correlation function [g1(�)] varied linearly with q2,indicating translational diffusion of the scatterers (q being the mag-nitude of the scattering vector given by q = [4�n sin �/2]/�, wheren is the refractive index of the solvent, � is the wavelength of laserlight, and � is the scattering angle). From the slope of the � vsq2 plots, the apparent diffusion coefficient values were estimatedand from these values the apparent equivalent hydrodynamicradii of the micelles were calculated using the Stokes–Einsteinrelation.

The intrinsic viscosities of the individual copolymer orcopolymer–surfactant mixture solutions were calculated from theextrapolation of reduced viscosities to zero concentration. The rela-tive viscosities were obtained from the measured flow times usingUbbelhode suspended level viscometers. Three consecutive flowtimes, agreeing within ±0.02 s were recorded and the mean flowtime was considered. The flow times were in the range of 220–360 sand therefore no kinetic corrections were made. The flow volumewas greater than 5 cm3, making drainage corrections unimpor-tant. Shear corrections were not taken into consideration becausethe obtained intrinsic viscosities were always less than 3 dl g−1.The temperature during the measurements was maintainedto ±0.01 K.

In solubilization experiments, 5.0 mg of the dexametha-sone was added to 10 cm3 of each of either copolymer orcopolymer–surfactant solutions. This amount far exceeds its sol-ubility in water so that saturation solubilization is ensured. Thesolutions were stirred at room temperature for 48 h. After equilib-rium, the solutions were centrifuged at 10,000 rpm for 30 min andthen the supernatant solutions were filtered through a Whatmanpaper (40). Thus obtained clear solutions then used for the UV–Vismeasurements using Shimadzu UV-160A UV-Vis spectrophometerequipped with quartz cells (1 cm path length). The UV absorbanceat 242 nm and 299.15 K was measured. The amount of dexam-ethasone solubilized in each solution was determined by using thecalibration curve (developed for aqueous solutions of drug in theconcentration range of 0.005–0.015 mM).

Hydrogels of agar agar, were prepared either in dexamethasoneloaded copolymer solutions alone or copolymer–surfactant solu-tions. The 3% (w/v) agar agar solutions were warmed for 10 min andthen poured into a petridish in hot condition. The gel was allowedto form a dry optically clear thin film for 4 h.

3. Results and discussion

3.1. Surface tension isotherms

The surface tension isotherms for the copolymer in water or200 mM NaCl or in the presence of surfactants at 303.15 K areshown in parts a–c of Fig. 1. The concentrations of the surfac-tants were selected so as to cover the range from unimers to theirmicelles. The isotherms for the individual surfactant solutions arealso shown in the figure. The CMC values for the individual surfac-tants in water were: SDS, 8.30 (8.20 [17] and 8.30 [18]), DTAB, 150(152 [19] and 160 [20]) and TX-100, 0.33 (0.33 [19], 0.325 [21]) andthus agree well with the literature reported values.

The surface tension isotherms of the copolymer were typ-ical. The surface tension of water was decreased substantiallyeven at very low concentration, indicating that the copolymermolecules have high surface activity and wetting action. PluronicEPE copolymer aqueous solutions usually show two break points[22] and the same has also been observed in the present study.

The first break point indicates the rearrangement of copolymermolecules at the complete coverage at air/water interface andwhile second point represents the concentration beyond whichtrue micelles are formed. Our observed CMC value of 0.041 mM

56 A.D. Thummar et al. / Colloids and Surfaces A: Physicochem. Eng. Aspects 386 (2011) 54– 64

Table 1Break points as determined from surface tension isotherms of E37P58E37–surfactant mixed systems in water and 200 mM NaCl at 303.15 K.

Surfactant Conc. (mM) Break points (mM)

I II

Water 200 mM NaCl Water 200 mM NaCl

SDS0 2.00 × 10−3 1.85 × 10−5 0.042 ± 0.01 0.023 ± 0.0020.03 2.32 × 10−3 – 0.079 ± 0.010.17 2.68 × 10−3 1.22 × 10−4 0.11 ± 0.01 0.013 ± 0.0010.35 2.83 × 10−3 – 0.15 ± 0.01 –0.87 3.20 × 10−3 – 0.20 ± 0.02 –1.73 4.62 × 10−3 – 0.59 ± 0.06 –

DTAB0.32 3.22 × 10−3 – 0.088 ± 0.01 –1.62 3.83 × 10−3 9.82 × 10−4 0.13 ± 0.01 0.008 ± 0.0013.24 7.18 × 10−3 0.18 ± 0.01 –

TX-100−3

fldtttc

tttttbttsic

c2tavtfvticl(scttbD

3p

mam

0.003 2.40 × 10 –

0.03 3.34 × 10−3 –

0.16 4.51 × 10−3 –

or E37P56E37 in water at 303.15 K is in good agreement with theiterature value of 0.038 mM [23]. The addition of 200 mM of NaClecreased both the break points and the same can be attributedo the fact that the salt molecules which themselves are preferen-ially hydrated decrease the solubility of the hydrophilic E part ofhe copolymer and hence facilitate the micelle formation at lowoncentrations.

The effect of surfactants on the break points of the surfaceension isotherms is summarized in Table 1. Addition of surfac-ants resulted in the increase in the break points. Considering thathe first break point marks the initiation of interaction betweenhe two components, while the second break point indicateshe saturation of interaction, the difference between the tworeak points can be taken as the amount of surfactant boundo copolymer chains. A perusal of data from Table 1 reveal thathe amount of bound surfactant irrespective of their ionic nature,ystematically increased with the increase in their concentration,ndicating that the binding of surfactants to copolymer chains isooperative.

Another interesting parameter is the CMC/C20, where C20 is theoncentration at which surface tension of water is decreased by0 units. A high value of this parameter in general is attributedo more adsorption tendency of the surface active species atir/water interface than their micellization in bulk. The CMC/C20alues for example are usually very low (1–2) for ionic surfac-ants, (10–20) for nonionic surfactants [21] and very high (∼104)or hydrophilic EPE copolymers [22]. Upon comparison of CMC/C20alues for copolymer solution with the copolymer–surfactant mix-ure solutions (corresponding to surfactant low concentrations),t was observed that the ratio values increased from 112.5 (foropolymer) to 282.7 (TX-100), 748 (SDS) and 1167 (DTAB). Fol-owing conclusions can be drawn from the above observations:i) the copolymer–surfactant species would prefer adsorption aturface than association in bulk, (ii) nonionic TX-100 moleculesan be easily incorporated into copolymer chains, (iii) the interac-ion between copolymer and DTAB molecules is weak as comparedo copolymer and SDS system mainly because of partial repulsionetween the protonated E segments of copolymer and cationicTAB molecules.

.1.1. Copolymer–surfactant mixed micelles and interactionarameter

RST formulations have been applied to copolymer–surfactantixtures not only to calculate the interaction parameter (ˇ) but

lso to adjudge the nature of interaction [24]. Considering that theixing of the two components is consistent at all mole fractions, the

0.10 ± 0.01 –0.12 ± 0.02 –0.23 ± 0.03 –

mole fraction of surfactant (1) in the mixed micelles, X1 is calculatedby Eq. (1):

X21 ln(˛1CMCmix/X1CMC1)

(1 − X1)2 ln(((1 − ˛1)CMCmix)/(1 − X1)CMC2)= 1 (1)

where ˛1 and CMC1 are mole fraction and CMC of component (1)in the solution, CMCmix is the CMC of the mixture. The interac-tion parameter then is evaluated using Eq. (2) by an iterativeprocedure,

ˇ = ln(˛1CMCmix/X1CMC1)

(1 − X1)2(2)

Similarly, the activity coefficients, fi of the surfactant in themixed micelles are calculated using Eqs. (3) and (4),

f1 = exp[ˇ(1 − X1)2] (3)

and

f2 = exp(ˇX21 ) (4)

The CMCmix of copolymer–SDS and –DTAB mixtures preparedin different mole ratios were determined from the surface tensionisotherms. Typical plots for copolymer–SDS systems are shown inFig. 2, while similar isotherms for copolymer–DTAB are shown inFig. S1 of supplementary material.

The ideal CMC values were calculated by assuming a simple idealmixing of the two components based on phase separation model.According to this model, the CMCmix is expressed in terms of CMCsof individual components using the equation proposed by Clint,

1CMCmix

= ˛1

C1+ 1 − ˛1

C2(5)

The comparison of experimental and calculated CMCmix val-ues at different copolymer mole fractions are shown in part b ofFig. 2 and Fig. S1 of supplementary material. The values of ˛1, X1,ˇ, f1 and f2 are listed in Table 2. It can be seen that the CMCmixand micellar mole fraction increase with the increase in the molefraction of ionic surfactants. The values are negative and rangedbetween −3.5 and −3.8 for copolymer–SDS system and −3.0 and−4.0 for copolymer–DTAB mixtures. Otherwise the mixtures arecharacterized by a mean value of −3.7. The negative values ingeneral indicate over all favorable interactions (synergistic behav-

ior) between the two components. The activity coefficients are lessthan unity and it was observed that the activity coefficients ofionic surfactants decrease with the increase in their mole fraction.The activity coefficients are unit less thermodynamic quantities

A.D. Thummar et al. / Colloids and Surfaces A: Physicochem. Eng. Aspects 386 (2011) 54– 64 57

30

35

40

45

50

55

60

65

7030

35

40

45

50

55

60

65

7030

35

40

45

50

55

60

65

70

1×103

c

1×1001×10-31×10-6log[E37 P58 E37 ], mM

b

γm

Nm

-1a

Fig. 1. Effect of added surfactant concentrations (in mM) on the surface ten-sion isotherms of E37P58E37 solutions in water and 200 mM NaCl at 303.15 K: (a)E37P58E37–SDS in water: (�) 0, (�) 0.03, (�) 0.17, (♦) 0.35, (�) 0.87, (�) 1.73: in200 mM NaCl: (©) 0, (�) 0.17, (�) SDS in water; (b) E37P58E37–DTAB in water: (�) 0,(E

auiissattbssu

30

35

40

45

50

55

60

65

1.00.80.60.40.20.00

1

2

3

4

5

6

7

8

9

10

a

γm

Nm

-1

Logmixture, mM1×10-3 11×10-61×10-9

b

CM

C, m

M

E37 P58 E37 Mole fraction

Fig. 2. (a) Surface tension isotherms of copolymer–surfactant mixtures at variousmole fractions (˛1) of sodium dodecyl sulfate in water at 303.15 K: (�) 1.0, (©) 0.9,(�) 0.8, (�) 0.6, (�) 0.4, (�) 0; (b) CMCs of mixed surfactant systems of E37P58E37–SDS

m

�) 0.32, (�) 1.62, (♦) 3.24: in 200 mM NaCl: (©) 0, (�) 1.62: (�) DTAB in water; (c)37P58E37–TX-100 in water: (�) 0, (©) 0.003, (�) 0.03, (�) 0.16: (�) TX-100 in water.

nd have a value of unity in an ideal solution. Any deviation fromnity values indicates the increase of either attractive or repulsion

nteractions among the components. The favorable or attractiventeraction between the nonionic copolymer molecules and ionicurfactant molecules are facilitated by the fact that bound ionicurfactant molecules are separated by E and P chains of copolymernd hence shield the repulsive head group· · ·head group interac-ions. Azzam [25] and Couderc et al. [13,15] have also calculatedhe activity coefficients for pluronic E18P31E18–sodium dodecyl-enzene sulfonate, E18P31E18–glycol mono-n-dodecyl ether mixed

ystems and noted similar trends in the activity coefficients ofurfactants with its mole fraction in the mixed micelles. A betternderstanding of the nature of interactions through the treat-

at 303.15 K: Points are experimental data, the solid line corresponds to calculatedvalues according to the non-ideal mixed micelle model ( = −3.6) and the dashedline represents the values for the ideal solution ( = 0).

ment of interaction parameters and activity coefficients wouldrequire systematic results from mixed systems consisting of dif-ferent copolymers with variation in the hydrophobic–hydrophilicratio and surfactants with different head groups.

3.1.2. Surface active parametersSurface active parameters namely the effectiveness of surface

tension reduction, �CMC, adsorption efficiency, pC20, surface excess,� max and minimum area per molecule, Amin were calculated fromthe well known definitions following Gibbs equation [21]. pC20is the negative logarithm of total concentration in the mixture atwhich surface tension value of water is reduced by 20 units and thesurface excess concentration, � m and Amin for pure componentswere calculated by equations,

�m = − 12 × 2.303RT

(∂�

∂log C

)T

(6)

and

Amin = 1018

N�(7)

where R = 8.31 J mol−1 K−1, T = absolute temperature in K,� = surface tension values in mN m−1, C = concentration inmol dm−3 and N = Avogadro’s number. � m is expressed in

58 A.D. Thummar et al. / Colloids and Surfaces A: Physicochem. Eng. Aspects 386 (2011) 54– 64

Table 2Mole fraction of ionic surfactant (˛1), critical micelle concentration of mixed systems of E37P58E37–ionic surfactants, ideal CMC, micellar mole fraction (X1), interactionparameter (ˇ) and activity coefficients (f1 and f2) at 303.15 K.

˛1 CMC (mM) X1 f1 f2

Experimental Ideal

SDS0.0 0.04 ± 0.003 0.04 – – – –0.4 0.06 ± 0.003 0.07 0.0630 −3.5 0.0482 0.98640.6 0.09 ± 0.004 0.10 0.1106 −3.6 0.0569 0.95660.8 0.15 ± 0.006 0.20 0.1767 −3.7 0.0818 0.89110.9 0.25 ± 0.010 0.39 0.2400 −3.8 0.1130 0.80451.0 8.30 ± 0.100 8.30 – –DTAB0.0 0.04 ± 0.003 0.04 – – – –0.4 0.07 ± 0.003 0.07 0.0293 −3.0 0.0601 0.99740.6 0.09 ± 0.004 0.10 0.0909 −3.9 0.0396 0.9682

mmaat

�

c

mabnettebtcaiidAi

TMsE

0.8 0.16 ± 0.006 0.20

0.9 0.27 ± 0.010 0.40

1.0 15.0 ± 0.450 15.0

ol cm−2. The slope values (∂�/∂log C) corresponding to thearked linear lines of surface tension isotherms of part a of Fig. 2

nd Fig. S1 of supplementary material have therefore been used inbove calculations. Eq. (6) has been modified [25] to incorporatehe mole fraction of ionic surfactants, X1 in the mixed micelle to,

m = − 1(2 − X1) × 2.303RT

(∂�

∂log C

)T

(8)

The surface active parameters thus calculated foropolymer–ionic surfactant mixtures are summarized in Table 3.

It can be seen that the adsorption efficiency, pC20 of the copoly-er chains is high as compared to SDS or DTAB molecules. The

dsorption efficiency values for the mixed systems however lie inetween to that of respective pure components. It is interesting toote that the efficiency for the mixture solutions containing high-st mole fraction of respective ionic surfactants was twice morehan their pure values. This trend supports our earlier observationhat the mixed copolymer–ionic surfactant complexes have prefer-ntial tendency for adsorption at interface over the association inulk. �CMC value is a direct measure of the effectiveness to reducehe surface tension value of water and a perusal of the data indi-ates that the copolymer and ionic surfactants are equally effectives far as their wetting behavior is concerned. The initial addition ofonic surfactants even though decreased the �CMC and the same is

ncreased at surfactant rich mixtures. The increased adsorption ten-ency of copolymer–surfactant complexes is reflected in increasedmin for the mixtures and surface excess concentration with the

ncrease in ionic surfactant mole fractions.

able 3ole fraction of ionic surfactant (˛1), adsorption efficiency (pC20), effectiveness of

urface tension reduction (�CMC), surface excess (� m), and minimum area (Amin) for37P58E37–ionic surfactants mixtures at 303.15 K.

˛1 pC20 �CMC

(mN m−1)� m × 1010

(mol cm−2)Amin (nm2)

SDS0 7.2 37.9 1.75 ± 0.1 0.95 ± 0.060.4 6.7 35.4 2.08 ± 0.1 0.80 ± 0.020.6 6.5 33.9 2.33 ± 0.1 0.71 ± 0.030.8 6.0 34.5 2.41 ± 0.1 0.69 ± 0.030.9 5.8 36.1 2.53 ± 0.1 0.66 ± 0.041 2.8 37.5 2.79 ± 0.1 0.60 ± 0.04DTAB0 7.2 37.9 1.75 ± 0.1 0.95 ± 0.060.4 7.1 33.0 2.16 ± 0.1 0.77 ± 0.030.6 6.7 34.0 2.26 ± 0.1 0.74 ± 0.030.8 6.0 34.8 2.32 ± 0.1 0.72 ± 0.030.9 5.6 36.7 2.34 ± 0.1 0.71 ± 0.041 2.7 37.3 2.93 ± 0.1 0.57 ± 0.20

0.1477 −3.9 0.0578 0.91790.2069 −4.0 0.0792 0.8415– – – –

3.2. DLS measurements

3.2.1. Intensity distributions of apparent hydrodynamic radiusThe intensity fraction distributions of the apparent hydrody-

namic radius, Rh of copolymer–surfactant mixtures prepared witha fixed concentrations of either 7.7 and 11.5 mM of copolymer andvarying mole fractions of the three surfactants, Xsurf (Xsurf = molesof surfactant/moles of surfactant + moles of copolymer) were con-structed. The surfactant concentrations selected covered both preand post micellar range. Typical distribution profiles for 7.7 mM ofcopolymer and at different Xsurf values for SDS, DTAB and TX-100are shown in parts a–c of Fig. 3. Similar distributions for 11.5 mM ofcopolymer–surfactant solutions are shown in Fig. S2 of supplemen-tary material. A perusal of profiles reveals that the distributionsare unimodal in nature across the mole fraction range for thethree different mixed systems implying the presence of singletype of associates. The size of the associates, however decreasedwith the initial addition of the surfactants and reaches a pseudoplateau value at higher mole fractions of the surfactants. The molarratios corresponding to the plateau values showed the order: TX-100 < SDS < DTAB, supporting our earlier observation that TX-100molecules interact and incorporate into copolymer micelles easilyand while the copolymer–DTAB interactions interact least.

3.2.2. Variation of hydrodynamic radiusCopolymer aqueous solutions: The average translational diffusion

coefficients were measured across the concentration range in wateras well as in 200 mM NaCl at 303.15 and 313.15 K and the sameare plotted as a function of copolymer concentration in Fig. 4. Thediffusion coefficients of associates increased linearly with the con-centration and the dependence could be fitted to an equation oftype:

D = D0(1 + kD · C) (9)

where D is the effective z-average translation diffusion coeffi-cient at concentration C, D0 is the z-average diffusion coefficient atinfinite dilution and kD is the diffusion virial coefficient. The hydro-dynamic radius, Rh of the associates then was calculated from the D0values through Stokes–Einstein relation, Rh = kT/(6�D) assuminga spherical shape to the micelles.

The D0 and Rh values thus obtained are 1.58 × 10−7 and1.44 × 10−7 cm2 s−1; 176 and 192 A at 303.15 and 313.15 K respec-tively. By using the relation R3

h = 3[]Mm/10�NA, the average

micellar weight Mm was calculated. The mass average associationnumber, n of the micelles was expressed as the ratio between Mm

and molar mass of the copolymer and the same were found to be724 and 817 at the above two temperatures. The n values calcu-

A.D. Thummar et al. / Colloids and Surfaces A: Physicochem. Eng. Aspects 386 (2011) 54– 64 59

0

2

4

6

8

100

2

4

6

8

1000010001001010.10

2

4

6

8

XDTAB

= 0.806

b

Inte

nsity

(a.u

.) XDTAB

= 0.790

XDTAB

= 0.757

XDTAB

= 0.712

XDTAB

= 0.628

XDTAB

= 0.513

XDTAB

= 0.294

XDTAB

= 0

XSDS

= 0.689

XSDS

= 0.645

XSDS

= 0.565

XSDS

= 0.473

XSDS

= 0.313

XSDS

= 0.094

a

XSDS

= 0

c

Rh , nm

XTX-100 = 0.661

XTX-100 = 0.547

XTX-100 = 0.287

XTX-100 = 0.058

XTX-100 = 0.017

XTX-100 = 0

Fig. 3. Normalized intensity distributions of apparent hydrodynamic radius, Rh foraa7

livltfspw1o

121086421.2

1.6

2.0

2.4

2.8

3.2

3.6

4.0

4.4

D ×

107

, cm

2 .s-

1

[E37P58 E37], mM

_

queous solutions of E37P58E37–surfactant complexes in aqueous and 200 mM NaCls a function of surfactant molar ratios at 303.15 K (copolymer concentration are.7 mM fixed).

ated by this way seem to be overestimated and the overestimations perhaps is due to the fact that Rh value was estimated from D0alues. There exist few literature studies dealing with the micel-ar characteristics of E37P56E37. Foster et al. [26] had reported fromheir detailed analysis of SANS data employing dense spherical coreorm factor with Gaussian statistics, for a 7.7 mM P105 aqueousolution at 293.15 K that the solutions consist only few unimers

er micelle (∼2.9) even though the interaction radius of micellesas 110.4 A. Alexandridis and Yang [27] analyzed SANS spectra of

2.3 mM of E37P56E37 aqueous solutions in the temperature rangef 303.15–333.15 K. A core–corona form factor and hard sphere

Fig. 4. Plots of translational z-average diffusion coefficient (D) versus copolymerconcentrations in water (�, ©) and 200 mM NaCl (�, �) at 303.15 K (closed symbols)and 313.15 K (open symbols). The solid lines are the fitted values.

structure factors were considered in treating the spectra. It wasconcluded that the Rhs values varied very little (84–86 A) and whilethe aggregation number increased from 50 to 78 in the temperaturerange of their study. Even though two independent groups [28,29]had reported the Rh values (from DLS data) for 7.7 mM solutions ofthe same copolymer in water, the values at 298.15 K for examplevaried from 90 A [28] to 79 A [29]. These discrepancies can be dueto the in-homogeneity in the composition of the samples preparedfrom different batches. Moreover, one has to be extremely carefulin studying the pluronic copolymer aqueous solutions at differenttemperatures because, each of the solutions have a particular crit-ical micellization temperature (CMT) and CMTs for this copolymersolutions ranged from 305.15 to 292.65 K for concentrations rang-ing from 0.01 to 3.85 mM [23]. Therefore, CMT for 7.7 and 11.5 mMaqueous solutions are to be less than 292.65 K. In view of this, theobservation by Foster et al. [26] that 7.7 mM P105 aqueous solu-tions at 293.15 K contain only unimeric molecules, in our opinionis highly suspected.

The various micellar parameters namely z-average diffusioncoefficient, hydrodynamic radius, Rh, polydispersity, P and massaverage association number, n for the E37P56E37 micelles in aque-ous solutions are listed in Table 4. It can be seen from the datathat Rh of the micelles is increased with the increase in the tem-perature in water and while decreased in 200 mM NaCl solutions.DLS data treatment considers that the hydrodynamic radius of themicelles includes the hydrated water. Therefore Rh and associationnumber, n values obtained from DLS data are always higher thanthose obtained from SANS measurements [27]. The decrease in thesize in the presence of 200 mM NaCl indicates that the micelleshave a compact configuration in salt solutions due to the decreasedsolubility of hydrophilic E chains.

Copolymer–surfactant mixture solutions: We have examined theeffect of added SDS, DTAB and TX-100 on copolymer micelles bymeasuring the translational diffusion coefficients at fixed copoly-mer concentrations of either 7.7 or 11.5 mM in 200 mM NaClsolutions. The variation of apparent hydrodynamic radius, Rh val-ues as function of surfactant concentrations is shown in Fig. 5. TheRh values systematically decrease with the addition of surfactants.The decrease is very sharp initially followed by a smooth trend at

high surfactant concentrations. The decrease in the micellar size ingeneral indicates that the copolymer bound surfactant moleculesfacilitate the shifting of the equilibrium: unimer ↔ micelle to theleft and thus surfactant addition induces dissociation of copoly-

60 A.D. Thummar et al. / Colloids and Surfaces A: Physicochem. Eng. Aspects 386 (2011) 54– 64

Table 4Micellar parameters for copolymer solutions in aqueous media.

Conc. (mM) D × 107 (cm2 s−1) Rh (A) []a (cm3 g−1) P# n D × 107 (cm2 s−1) Rh (A) []a (cm3 g−1) P# n

T = 303.15 K T = 313.15 K

Water7.7 2.89 96

79 [23]7.3 0.102 118

71 [23]2.90 122 8.4 0.163 210

11.5 2.96 9484 [28]

7.3 0.123 11050 [28]

3.00 11986 [28]

8.4 0.204 19557 [28]

200 mM NaCl7.7 3.44 80 5.5 0.006 90 3.46 102 6.8 0.015 15111.5 3.89 71 5.5 0.008 63 3.78 93 6.8 0.052 115

a

M so

mm1moi[

FtE13

Obtained by extrapolation of reduced viscosity to zero concentration.# P = 〈(D − D)

2〉/D2. Ref. [23] data at T = 298.15; Ref. [28] Rhs from SANS for 12.3 m

er micelles. The reduction of micellar size has been found to beore in the presence of ionic surfactants than the nonionic TX-

00 and therefore it can be stated that copolymer–TX-100 mixed

icelles resist the break down. The destabilization and suppression

f EPE copolymer micellization in the presence of ionic and non-onic surfactants has also been well documented in the literature30–33].

4.03.53.02.52.01.51.00.50.030

40

50

60

70

80

90

100

110

2.01.81.61.41.21.00.80.60.40.20.0

65

70

75

80

85

90

95

100

105

110

115

120Rh ,

Aο

Concentration, mM

ig. 5. Variation of hydrodynamic radius, Rh as a function of surfactant concen-ration: (a) 7.7 mM E37P58E37–SDS (�, �); 11.5 mM E37P58E37–SDS (�, ©); 7.7 mM37P58E37–DTAB (�, �); 11.5 mM E37P58E37–DTAB (�, ♦); (b) 7.7 mM E37P58E37–TX-00: (�, �); and 11.5 mM E37P58E37–TX-100 (�, �): at 303.15 K (closed symbols) and13.15 K (open symbols).

lution.

3.3. Dilute solution viscosity measurements

Dilute solution viscosity measurements were carried out toobtain indirectly the information on the hydrodynamic size ofmicellar aggregates in terms of intrinsic viscosities, []. The val-ues of [] for pure copolymer solutions and copolymer–surfactantmixture solutions in water as well as in 200 mM NaCl solutionswere obtained from the extrapolation of reduced viscosities to zeroconcentration following Huggins equation,sp

C= [] + kH[]2C (10)

where sp/C = reduced viscosity, [] = intrinsic viscosity,kH = Huggins constant, and C = concentration in g dl−1. The variationof intrinsic viscosities and Huggins constant as a function of surfac-tant concentration is shown in Fig. 6. It can be seen that irrespectiveof the ionic or nonionic nature of the surfactant, intrinsic viscosityvalues increase with the increase in the surfactant concentrationswhile the Huggins constant values showed a decreasing trend. Wemake here an attempt to explain these trends. One would normallyexpect that the intrinsic viscosities of the micelles decrease uponthe addition of the micelle destabilizing surfactants. However, thevalue of intrinsic viscosity which measures the hydrodynamic vol-ume of copolymer–surfactant mixtures depends on several factors.Important of them include the dimensions of the hydrophobic

core part, hydrophilic shell part of the micelles and number ofunimers, the equilibrium constant of micelles ↔ unimer, amountof hydrated water of both the micelles and unimers, the hydratedwater of surfactant micelles, etc. As described and discussed in

40353025201510505

6

7

8

9

10

11

12

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

[η],

cm3 .

g-1

Surfactant concentration, mM

kH

Fig. 6. Plot of intrinsic viscosity, [] (closed symbols) and Huggins constant (kH,(open symbols)) versus surfactant concentrations in water and 200 mM NaCl solu-tions at 303.15 K: in water: E37P58E37–(�) SDS, –(�) DTAB, –(�) TX-100; in 200 mMNaCl: E37P58E37–(�) SDS, –(�) DTAB.

A: Ph

slmemh

3r

ibrwofobaddtb

mttdcogscidcicdtc

Ft(

A.D. Thummar et al. / Colloids and Surfaces

ections, the copolymer–surfactant mixture solutions consistargely the surfactant bound unimers or micelles, and the mixed

icelles consist majority of surfactant molecules. These species arexpected to be highly hydrophilic as compared to pure copolymericelles and therefore the copolymer–surfactant solutions have

igh intrinsic viscosities.

.4. Solubilization and immobilization of dexamethasone and itselease profiles in copolymer–surfactant mixtures

The encapsulation of hydrophobic drugs especially doxorubicinnto hydrophobic cores of copolymer micelles to enhance its solu-ility in aqueous phase and its clinical applications, has been welleported [16]. Dexamethasone has a partial solubility 0.234 mM inater [34] and its solubility could be increased by copolymer aque-

us solutions. The plot of the amount of the drug solubilized as aunction of copolymer concentration is shown in Fig. 7. The CMCf the copolymer in drug aqueous solutions can be determinedoth from this plot and also by surface tension measurements. Anverage CMC value of 0.022 mM was noted for the copolymer inrug solutions as compared to a value of 0.041 mM in water. Theecrease in CMC gives a direct indication that upon the incorpora-ion of the hydrophobic drug molecules the copolymer moleculesecome more hydrophobic.

The fraction of the drug in the micellar solutions, Pm was esti-ated by the equation, Pm = (1 − Cw/Cw+m) where Cw and Cm are

he concentration of drug in aqueous and water phase respec-ively. The Cw value was fixed at the maximum solubility of therug in water, i.e. 0.255 mM. The summary of Cw, Cm and Pm foropolymer–surfactant mixture solutions prepared with a 7.7 mMf copolymer and varying amounts of individual surfactants isiven in Table 5. A comparison of concentration of dexametha-one in micellar phase for the copolymer solutions alone andopolymer–surfactant mixtures, revealed that Cm increased withncrease in copolymer concentration and while the same getecreased with the surfactant concentrations. When we consideropolymer micelles in water alone, their micellar number densityncreases with its concentration and hence more drug molecules

an be partitioned into micellar phase. While the situation is quiteifferent and in fact reverse in copolymer–surfactant systems. Morehe added surfactant, the more would be the destabilization of theopolymer micelles. There by, such copolymer–surfactant systems

ig. 7. Amount of solubilized dexamethasone as a function of E37P58E37 concentra-ions (the inlet figure represents UV-spectra for different concentrations of the drug0.005–0.015 mM)).

ysicochem. Eng. Aspects 386 (2011) 54– 64 61

provide an ideal media in which presolubilized drug substances bycopolymer micelles can be extracted by simple addition of surfac-tants.

3.4.1. Hydrogels as matrix for drug immobilization and releaseA literature survey shows that in practical clinical applica-

tions, dexamethasone has been introduced in solution or dispersionform by direct injection. This procedure however requires largedose, repeated injections are needed to ensure therapeutic lev-els over an extended period of time and this procedure causes thereduction in patient compliance and/or increased likely-hood ofcomplications [35]. To circumvent these problems, developmentof control release systems especially using hydrogels as matrix fordrug immobilization and its release is highly necessary. Surfac-tant aided immobilization and control release of the drugs fromagarose hydrogels has already been reported [36,37]. The micellesof E37P56E37 in water have been employed to immobilize doxoru-bicin and its release kinetics were monitored using acoustic waves[38,39]. Therefore we thought it interesting to try and evaluateagar agar based hydrogels prepared in either with copolymer aque-ous solution alone or copolymer–surfactant mixture solutions. Theaddition of surfactants can aid the fast release of solubilized drugmolecules.

A typical profile showing the dependence of the percentage offraction of dexamethasone released as a function of time for vary-ing concentrations of copolymer in aqueous solutions is depicted inFig. 8. Similar profiles were observed for the copolymer–surfactantmixtures and the same are given in Fig. S3 of supplementary mate-rial. The profiles are typically of inverse L shape wherein the fractionof released amount increased almost linearly with time before itplateaus at longer times. The fractional release of the drug interest-ingly was higher in 1.54 mM copolymer solutions and the same isdecreased with the increase in its concentration. The time requiredto reach the plateau value was more for high concentration. Theseresults are consistent with the data on fraction of the drug in themicellar phase, which increased with the increase in copolymerconcentration (Table 5). More the amount of the micellar fraction,strong would be the copolymer–drug interactions and less wouldbe its release.

The release profiles presented a reverse trend for the

copolymer–surfactant solutions. The fraction of released drug notonly increased with the increase in the surfactant concentration butalso time required for attaining the plateau value was decreased.Assuming a constant drug diffusion coefficient, D, Ritger and Peppas

2502001501005000

10

20

30

40

50

60

70

80

90

100

% F

ract

ion

of d

rug

rele

ased

t, min

1.5 mM3.1 mM 4.6 mM6.2 mM7.7 mM

Fig. 8. Percentage fraction of drug released as a function of time from differentconcentrations of E37P58E37 aqueous solutions at 303.15 K.

62 A.D. Thummar et al. / Colloids and Surfaces A: Physicochem. Eng. Aspects 386 (2011) 54– 64

Table 5Solubilized dexamethasone amount, micellar phase Cm (all in mM) and fraction of dexamethasone in micellar phase, Pm for copolymer–surfactant mixtures in water at303.15 K.

E37P58E37 in water 7.7 mM E37P58E37–SDS

Conc. Amount of drugsolubilized

Cm Pm Surf. conc. Amount of drugsolubilized

Cm Pm

0.000 0.255 – 3.468 1.223 0.968 0.7930.009 0.306 – 6.935 1.147 0.892 0.7780.012 0.331 – 13.871 1.045 0.790 0.7580.015 0.331 – 17.338 0.917 0.663 0.7260.031 0.357 0.102 0.29 34.676 0.790 0.535 0.6790.046 0.382 0.127 0.31 7.7 mM E37P58E37–DTAB0.092 0.382 0.127 0.35 3.244 1.223 0.968 0.7920.123 0.408 0.153 0.37 8.110 1.172 0.917 0.7820.154 0.408 0.153 0.39 19.465 1.070 0.815 0.7621.538 0.535 0.280 0.51 32.441 0.994 0.739 0.7433.077 0.713 0.459 0.65 51.906 0.866 0.612 0.7084.615 0.866 0.612 0.71 7.7 mM E37P58E37–TX-1006.154 1.019 0.764 0.75 0.077 1.249 0.994 0.7947.692 1.249 0.994 0.8 0.155 1.172 0.917 0.783

[d

waBa

l

tWrlmFt

F1

40] proposed following equation relating the fractional amount ofrug released (Mt/M∞) with the D:

Mt

M∞= 1 − 8

�2

∞∑n=0

1

(n + 1)2exp

{− (2n + 1)2D�2

l2t

}(11)

here l is the thickness of the hydrogel sheet, Mt and M∞ are themount of drug released at time t and at infinite time (i.e. 48 h).y taking only the first term in summation series and performing

logarithmic transformation, Eq. (11) can be simplified to,

n(

1 − Mt

M∞

)= ln

8�2

− D�2

l2t (12)

It can be seen from Eq. (12) that a plot of ln(1 − Mt/M∞) againstime t should yield a straight line with a slope equal to −D�2/l2.

e fitted the experimental values of the fractional amount of drugeleased from copolymer solutions (through Eq. (12) (as a semi-

ogarithmic plot)) by a linear regression based on least squares

ethod and the experimental and fitted values are shown inig. 9. Similar plots for the copolymer–surfactant mixture solu-ions are given in Fig. S4 of supplementary material. The results

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

t, min10070

y = - 0.026x + 0.341

y = - 0.023x + 0.218

y = - 0.020x + 0.142

y = - 0.018x + 0.093

ln ( 1

-Mt/M

α)

y = - 0.017x + 0.084

12045

ig. 9. Semi-logarithmic plots as per Eq. (12): E37P58E37 solution in water: (�).5 mM, (�) 3.1 mM, (�) 4.6 mM, (©) 6.2 mM, (�) 7.7 mM.

3.096 1.096 0.841 0.7669.288 0.994 0.739 0.74415.479 0.917 0.663 0.723

of variation of drug diffusion coefficient as a function of con-centration for the aqueous solutions of copolymer in water andcopolymer–surfactant systems are shown in Fig. 10. It can be seenthat the variation of drug diffusion coefficient presented contrast-ing trends. The drug diffusion in solutions can be considered toconsist of two individual processes namely, drug diffusion fromaqueous phase to micellar phase and micelle–micelle diffusion. Theoverall value of drug diffusion coefficient is therefore dependent onthe fraction of drug in aqueous phase as well as in micellar phase.In the low concentrations of the copolymer, the initial fraction ofdrug in aqueous phase and drug diffusion tendency would be high.The increase in the concentration of copolymer in solution howeverwould increase the number of micelles and decrease the fractionof drug in aqueous phase and drug diffusion coefficient. At con-centrations greater than 6.15 mM, the micelle–micelle diffusion gethindered due to their close interactions and under these conditions,the overall diffusion decreases and reaches a saturation value.

As compared to the decreasing trend of drug diffusion coef-ficient with the concentration in copolymer aqueous solutions,the increase of surfactant concentration in copolymer–surfactantmixtures increased the drug diffusion coefficients irrespective of

403020102

3

4

5

6

7

D ×

107 ,

cm

2 .s-1

Conc., mM

_

Fig. 10. Variation of drug diffusion coefficient, D as a function of E37P58E37 or sur-factant concentrations in E37P58E37–surfactant mixtures in water at 303.15 K: (�)E37P58E37 in water, (©) 7.7 mM E37P58E37–SDS, –(�) DTAB and –(�) TX-100.

A: Ph

iitimmtdssd

4

ehTstpaoottsohbmctussbdmso

A

Dp

A

t

R

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

A.D. Thummar et al. / Colloids and Surfaces

onic or nonionic nature of surfactants. This is remarkable andndicates that the fraction of free drug in aqueous phase sys-ematically increases with the surfactant addition. As discussedn previous sections, the surfactants destabilize the copolymer

icelles into unimeric species hindering the drug diffusion intoicellar phase. The increase in drug diffusion coefficient followed

he order: SDS > DTAB > TX-100. Therefore the copolymer micelleestabilization power of the three surfactants must also have theame order, as indeed explained in previous sections. The resultsuggested that copolymer–surfactant systems have potential asrug releasing agents from hydrogel media.

. Conclusions

The amphiphilic tri-block copolymer, E37P56E37 interacts coop-ratively with SDS, DTAB and TX-100 surfactants to form highlyydrophilic copolymer–surfactant complexes in aqueous media.he addition of surfactants to copolymer solutions decreases theurface tension drastically and results in many fold increase ofhe characteristic CMC/C20 value. The copolymer–surfactant com-lexes thus have a preferential tendency for the adsorption atir/water interface over their association in the bulk. The CMCf mixture solutions could be analyzed by regular solution the-ry to calculate the interaction parameter ˇ. The mean value ofhis parameter was ∼−3.7, indicating the presence of synergis-ic effects in copolymer–ionic surfactant mixtures. The addition ofurfactants has systematically decreased the hydrodynamic radiusf copolymer micelles and the intensity fraction distributions ofydrodynamic radius are found to be unimodal in nature. Theinding of surfactants to the unimeric and micellar forms of copoly-er molecules caused an increase in the CMC and destabilize the

opolymer micelles by shifting the equilibrium unimer ↔ micelleo left. Dexamethasone, an anti-inflammatory drug could be sol-bilized in copolymer as well as copolymer–surfactant mixtureolutions. An attempt was made to explore the drug solubilizedolutions and agar agar gels, useful as control release system. It haseen observed that the addition of surfactants has increased therug release rate. The drug diffusion coefficients have been deter-ined and the values of the same were found to increase upon

urfactant addition. The results of this study offer an alternate modef control release system for dexamethasone in aqueous media.

cknowledgement

Authors are thankful to Board of Research in Nuclear Science,epartment of Atomic Energy, Mumbai for providing financial sup-ort under grant No. 2006/37/4/BRNS/893.

ppendix A. Supplementary data

Supplementary data associated with this article can be found, inhe online version, at doi:10.1016/j.colsurfa.2011.06.027.

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