Journal of Colloid and Interface Science 398 (2013) 270–272

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Short Communication

Thermodynamic properties of aqueous PEO–PPO–PEO micelles with addedmethylparaben determined by differential scanning calorimetry

Andre Lamont Thompson, Brian James Love ⇑Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI 48109, USA

a r t i c l e i n f o

Article history:Received 27 October 2012Accepted 31 January 2013Available online 16 February 2013

Keywords:MicelleMethylparabenPerturbationAdditiveCompensation temperatureEnthalpyPluronic� P105

0021-9797/$ - see front matter � 2013 Elsevier Inc. Ahttp://dx.doi.org/10.1016/j.jcis.2013.01.064

⇑ Corresponding author. Address: 2644 Bob and Bett48109-2136, USA.

E-mail addresses: andrelt@umich.edu (A.L. ThompLove).

a b s t r a c t

DSC experiments were performed on aqueous solutions of PEO–PPO–PEO (P105) amphiphiles in the lowconcentration regime (0–1%) to resolve the critical micelle concentration (cmc) both neat and co-formu-lated with methylparaben (MP). Further work was done at 10% amphiphilic copolymer concentrationsand co-formulated with MP to resolve the variations in enthalpy. The compensation temperature,Tcompensation, was determined from the analyses for neat P105 as 293.9 K; adding MP raises this to 328.43 K.

� 2013 Elsevier Inc. All rights reserved.

1. Introduction

Considerable interest has evolved in packaging of organicswithin amphiphilic copolymer micelles in skin care, the life sci-ences, and colloid science [1]. The relative hydrophobicity, solubil-ity, and isoelectric point can affect how organics are partitionedwithin micelles [2,3]. There are larger issues relating the size of or-ganic flux to safe and effective dosing. But the rationale for under-standing how ternary additives affect the micelle formationenergetics is likely key to also resolving how formulated micellesperform as drug delivery vehicles.

Research on drug-loaded micelles has included rheology [4,5],DSC [6–8], SAXS [4,6,9], (SANS) [10] and cell culture studies [11].Sharma et al. studied in detail the structures evolving from addingorganics as perturbations to the ordered structures forming fromPEO–PPO–PEO based solutions as resolved by SAXS [6]. The pres-ence of the ternary constituents can alter the phase structure, swellthe micelle, and otherwise affect the energetics of micelle forma-tion. Generally, the presence of additives lowers the micelle forma-tion temperature and within the solubility limits of eachconstituent, adding more of it correlates with a larger response[6,10].

ll rights reserved.

y Beyster Bldg, Ann Arbor, MI

son), bjlove@umich.edu (B.J.

We have previously evaluated the enthalpy and structuralchanges in other amphiphiles such as Pluronic� F127 micelles byseveral methods [5,9]. The most remarkable changes noted bytime-resolved SAXS scanning through the micelle formation tem-perature, Tmicelle, was that neat F127 solutions formed micellesmore abruptly suggesting a nucleation-based mechanism. Addingmethylparaben, MP, softened the transition such that ordered mi-celle formation occurred at lower temperatures and the size of theenthalpy grew more systematically with changes in temperature.

Smaller micelle formation endotherms were noted in the pres-ence of the drug mimics. Combined, adding the ternary species tothe PEO–PPO–PEO solution altered both the structural disorderdepending on how it is partitioned and the micelle formation ener-getics. More hydrophobic species are more likely contained withinthe core, and more hydrophilic additives within the corona.

The energetics of micelle formation has also included an analy-sis of the enthalpy–entropy compensation that was first describedby Armstrong et al. [12]. DGmicelle is the free energy to take onemole of amphiphile dispersed in solution into the micelle phaseand is given by [12]

DGmicelle ¼ RTmicelle lnðcmcÞ

where Tmicelle is the _T micelle formation temperature, and cmc is thecritical micelle concentration. The enthalpy is the integral of eachmicelle formation endotherm. The entropy of micelle formation isextracted from rearranging the Gibbs Helmholtz equation to yield[12].

Fig. 1A. DSC results at low P105 content: the critical micelle concentration (cmc) of

A.L. Thompson, B.J. Love / Journal of Colloid and Interface Science 398 (2013) 270–272 271

DSmicelle ¼1

TmicelleðDHmicelle � DGmicelleÞ ð1Þ

Resolved at the micelle formation temperature at each concentra-tion of amphiphile used. From the determinations of DSmicelle andDHmicelle, a direct plot can resolve both the slope, identified as thecompensation temperature, Tcompensation, and the intercept (identi-fied as DH0). The compensation temperature represents the drivingforce for solute–solvent interactions and has been identified forneat amphiphiles in solution [8,13] and ionic liquids such as theGemini surfactants [1]. But resolving whether the ternary additivealso affected the compensation temperature has not been donewhich we set out to evaluate using Pluronic� P105 solutions andMP as a ternary additive. We studied this more directly usingamphiphilic triblock copolymers more volumetrically balanced be-tween the hydrophobic and hydrophilic elements.

neat Pluronic� P105 was noted between 0.2 and 0.4% by DSC.

Fig. 1B. Increasing the concentrations of P105 in water also increased the enthalpy(DH).

2. Materials and methods

PEO–PPO–PEO (Pluronic� P105: BASF Wyandotte MI) was ob-tained and used as received. Aqueous solutions of P105 were pre-pared according to ‘‘cold’’ processing methods [14] and formulatedin both a low concentration regime to resolve the critical micelleconcentration (cmc) and a higher concentration regime above 1%to probe the enthalpy of micellization. Methylparaben (Sigma–Al-drich) was added to aqueous solutions of varying P105. Two typesof formulation protocols were created. One fixed the P105 contentand varied the amount of MP. The other scheme used a fixedamount of MP and varied the P105 content.

As dispersions were produced, aliquots were extracted by syr-inge and deposited into DSC pans and tested using a TA Instru-ments Q-2000 DSC. Tests were conducted under nitrogen purgewhile the temperature was ramped from 0 to 40 �C at 10 �C/min,typical of other heating rates measures for other amphiphiliccopolymers. At least three replicates were evaluated performulation.

The onset and peak temperatures and the size of the endothermwere determined from the heat flow curve. As the P105 contentwas lowered, the micellization endotherm was smaller and atsome concentration, no endotherm is eliminated indicative of con-centrations below the critical micellization concentration, cmc.

3. Results and discussion

The influence of amphiphilic copolymer content by DSC is notedin Table 1. The temperature of the peak in the micelle formation isshifted slightly to lower temperatures (�2 �C) by adding morecopolymer to solution. The enthalpy is also reduced with lessP105 in solution since there are fewer micelles that can form inmore diluted mixtures of amphiphile in solution above the cmc.

With more dilution, there is some minor distortion in the DHpeak shape and at low enough concentration; there is an absenceof a micelle endotherm, shown in Fig. 1. The driving force is insuf-ficient to form micelles below some threshold and that demarca-tion is noted as the cmc. Fig. 1 shows the concentration

Table 1DSC results for 4–10%. P105 in H2O. Larger P105 concentrations show both a lowerTmicelle and a larger DH on a per gram basis.

P105 concentrations(% wt/v)

DH (J/g) Micelle formation temperature(�C)

4.0 2.667 20.546.0 3.667 19.208.0 4.499 17.97

10.0 5.29 17.42

dependence; the endotherm is suppressed at 0.4% wt/v. The P105cmc we resolved by DSC is slightly higher than that observed byAlexandridis et al. (0.3% wt/v) using UV–visible absorption spec-troscopy at 25 �C [15,16]. For the larger thermodynamic analysis,we used the cmc determinations from Alexandridis et al. [15,16]for determining DS and DG although similar trends arise usingthe cmc resolved by DSC.

Fig. 2 shows how adding MP to 10% P105 solutions withincreasing amounts of MP affected DH, which changed from350.8 to 318.2 kJ/mol when increasing amounts of MP was addedup to 1%. The presence of MP modulates the interaction energyof the mixtures and reduces the size of both the micelle formationendotherm and its peak temperature. A similar suppression wasnoted by Bouchemal et al. who characterized 1,2 propanediol inF127 and noted a �20% smaller endotherm when added as muchas 2.3% wt/v [7]. Kelarakis noted the near athermal micellizationin other diblocks [17,18]. If ternary compounds raise structural dis-order, the enthalpy contribution to micelle formation should bereduced.

At higher concentrations relative to the P105 solution concen-tration, the presence of MP cannot suppress micelle formation.80% of the original endotherm is still observable in 10% P105 with1% MP.

The larger question overall is how the relative impact of theternary additive affects the thermodynamics. To address this

Fig. 2. Increasing concentrations of MP in 10% P105 reduces both Tmicelle and DH.

Fig. 3. The enthalpy–entropy (DH–DS) compensation plot for P105, solutions bothneat (red with solid line) and co-formulated with MP (green dashed slope). (Forinterpretation of the references to color in this figure legend, the reader is referredto the web version of this article.)

272 A.L. Thompson, B.J. Love / Journal of Colloid and Interface Science 398 (2013) 270–272

question, extractions from the low concentration regime allow thedetermination of DG and direct measurements of the enthalpy ofmicellization. From these measurements, thermodynamic plots ofDH–DS can be produced both in a neat state and in the presenceof MP.

Fig. 3 is the enthalpy–entropy compensation plot for neat P105(red triangles) that yields a compensation temperature of 293.9 K.The compensation temperature determined for neat P105 is verysimilar to that resolved for the 8-series of Pluronic� (e.g. F68,F98) of 291.2 K [8]. Adding MP to the mixture triggers a subtle risein the compensation temperature from 293.9 K to 328.43 K (greensquares) treated as a separate dataset.

If the compensation temperature represents solute–solventinteractions, then the slopes of DH–DS curves with and withoutternary additives should be different. It seems appropriate thatadding a ternary species might influence the energetics of micelleformation. We compared our results to published work by Bouche-

mal et al. who using 1,2-propanediol with F127 using IsothermalTitraction Microcalorimetry. Interestingly, by using separate tem-perature compensation slope determinations, we observe fromtheir results a similar rise in the compensation temperature from293.3 to 316.5 K when co-formulated with 1,2-propanediol. Theiroriginal analysis reported a mean Tcompensation of 298.1 K [7].

4. Conclusions

We have probed how MP affects PEO–PPO–PEO micelle forma-tion in two different concentration regimes. Using DSC we con-firmed the cmc for P105 to be 0.4% wt/v at 26.3 �C, which is closeto but slightly larger than 0.3% wt/v at 25 �C of Alexandridis et al.[15,16] Increasing Pluronic� P105 from 4% to 10% reduced Tmicelle

and raised the endotherm. We propose that the enthalpy–entropycompensation plot for neat and MP-loaded solutions of Pluronic�

P105 can resolve the perturbation in the micelle energetics anddetermine Tcompensation of 293.9 K for neat P105; when also loadedwith MP, the modified Tcompensation is 328.43 K compared toBouchemal’s Tcompensation of 293.3 K for neat F127 and 316.5 Kwhen loaded with 1,2-propanediol [7]. The use of temperaturecompensation plots might resolve surfactant quality in formulateddispersions coerced into directed assembly. These results signifi-cantly help in understanding how organics mix within amphiphiliccopolymer micelles and dispersions. Our findings present a ratio-nale for understanding how the presence of a ternary additive, likeMP, affects the thermodynamics of the micelle formation and iskey to understanding how formulated micelles function as drugdelivery vehicles.

Acknowledgments

We acknowledge the Rackham Summer Institute at UM for sup-port and discussions with KA Juggernauth, NAK Meznarich, and KMBatzli during the project.

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