Temperature Evaluation of Curcumin Keto-Enolic Kinetics and Its

Article pubs.acs.org/JPCB

Cite This: J. Phys. Chem. B 2019, 123, 5641−5650

Temperature Evaluation of Curcumin Keto−Enolic Kinetics and Its Interaction with Two Pluronic Copolymers Adalberto Enumo, Jr.,† Christhian Irineu Dias Pereira,‡ and Alexandre Luis Parize*,† †

Polimat, Grupo de Estudos em Materiais Poliméricos, Departamento de Química, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina 88040-900, Brazil ‡ Departamento de Química, Universidade Estadual de Maringá, Maringá, Paraná 87020-900, Brazil

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S Supporting Information *

ABSTRACT: Curcumin (CUR), a natural hydrophobic polyphenol isolated from Curcuma longa, has been reported to possess two main equilibria in aqueous solutions, diketo/ keto−enolic tautomerism and self-aggregation. The thermodynamics of tautomeric equilibrium is well established; however, its kinetic parameters have been sparsely studied. Various efforts have been made to improve CUR solubility in aqueous media. We evaluated how the kinetics of tautomerism and the interaction of CUR with pluronic P123 and F127 copolymers in solution were affected by temperature, using UV−vis and fluorescence spectroscopies. Pluronic particle sizes with and without CUR were acquired by dynamic light scattering. The interaction in the solid state was verified by differential scanning calorimetry (DSC). The equilibrium rate that displaces to the diketo form increased fivefold when the temperature rose from 294 to 314 K with an activation energy of 61.2 kJ mol−1. The CUR solubility increased from 2.58 to 6.77 mg g−1 when incorporated in P123 and from 0.05 to 3.54 mg g−1 when incorporated in F127 with a change in the temperature from 298 to 314 K. This process had a Gibbs free energy of around −1 and −13 kJ mol−1 because of CUR solubilization into the inner core of pluronic micelles. Particle sizes of about 11 nm were obtained for both copolymers containing CUR in an aqueous solution above the critical micelle temperature. DSC measurements showed melting point depression of both CUR and F127. P123 presented no significant variation in the melting point because of its low melting enthalpy. The results indicate that temperature significantly influences CUR kinetic tautomerism and its interaction with both P123 and F127 copolymers. P123 presents a higher interaction in aqueous solution with CUR than F127. Both pluronics could contribute to a safer and more efficient CUR administration in the bloodstream.

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INTRODUCTION Curcumin (CUR, diferuloylmethane) is a yellowish polyphenolic compound extracted from turmeric rhizomes. It is widely used as a spice and a food colorant.1 Studies have presented the medicinal properties of this extract against microorganisms, cancer, and Alzheimer’s, and CUR is already used in Indian and Chinese traditional medicine as an antiinflammatory and for wound healing.2,3 The interaction of CUR with organelles and receptors could depend strongly on the diketo/keto−enolic equilibrium and its solubility and bioavailability. For example, it has been shown that the binding activity of a CUR analogue containing only the keto-form to amyloid-β (Aβ) aggregates is weaker than that of CUR derivatives with keto−enol tautomerism. Apparently, the enol form is the predominant factor during binding to Aβ aggregates, and thus enolization is crucial in the treatment of Alzheimer’s disease.4 Despite these therapeutic effects, this compound is poorly soluble in aqueous media, which self-aggregates into nonfluorescent parallel H-dimers.5 CUR presents a fast metabo© 2019 American Chemical Society

lism/excretion in physiological conditions and a rather low systemic bioavailability. This limits its body absorption, impairing its complete therapeutic action and interfering with the direct application of CUR in the bloodstream.6 Both the tautomerism and CUR self-aggregation phenomena are highly temperature-dependent in aqueous media. A rise in temperature favors the diketo form and inhibits the dimerization process.5,7 Although the thermodynamics involving the tautomeric equilibrium of CUR has been widely discussed,5,8,9 kinetic investigations of this equilibrium are relatively sparse. To overcome the dimerization process and to induce the presence of the enol tautomer into the physiological medium, several efforts have been made by researchers to produce new formulations to enhance the solubility, stability, and bioavailability of CUR in the bloodstream. Co-crystallization, Received: May 2, 2019 Revised: June 6, 2019 Published: June 11, 2019 5641

DOI: 10.1021/acs.jpcb.9b04150 J. Phys. Chem. B 2019, 123, 5641−5650

Article

The Journal of Physical Chemistry B

of AlPcCl in this copolymer. P123 was effective against S. aureus and C. albicans, depending on the drug concentration and illumination time.21,22 Here, we investigate the kinetic behavior of CUR tautomeric equilibrium and the method to prevent the aggregation of this compound in aqueous solutions by interactions with the triblock copolymers P123 (PEO20−PPO70−PEO20) and F127 (PEO100−PPO70−PEO100); the thermodynamic parameters of these processes are also evaluated.

amorphization, oil-in-water emulsification, and solid dispersion are worth mentioning.10 However, in the cases of cocrystallization and emulsification, a greater number of components are demanded, increasing the methodological complexity or requiring the use of sophisticated and expensive equipment, such as a spray dryer. The employment of the extrusion or similar techniques typically requires the rise in temperature near to CUR degradation, which makes the procedure difficult. Whereas solid dispersion is a versatile technique because of its simplicity without the use of other additives besides a cosolvent to the drug and a polymeric matrix, providing a good efficiency to maintain the free form of drugs, even in a physiological medium.11−13 In this context, Pires and co-workers investigated the binding between CUR and bovine serum albumin (BSA). BSA presents a considerable binding constant and reduces the CUR photodegradation kinetic process.14 Jin et al. made a formulation of CUR based on a complex with linear dextrin fabricated through the coprecipitation method. They observed an inclusion yield of 74%, and this complexation exhibited photochemical and thermal stability higher than that of pure ́ CUR.15 Martin-Belloso and colleagues incorporated CUR in the nanoemulsions of sodium alginate with corn oil containing three different additives (lecithin, Tween 20, and sucrose palmitate) in distinct concentrations. The nanoemulsions showed particle sizes ranging from 249 to 400 nm and zeta potential values from −35 to −85 mV with high encapsulation efficiencies. Furthermore, the nanoemulsions with lecithin did not undergo destabilization phenomena for almost 86 days, whereas those containing Tween 20 or sucrose were more rapidly destabilized.16 In this perspective, nonionic amphiphilic triblock copolymers formed by a poly(ethylene oxide) shell and a poly(propylene oxide) core (PEO−PPO−PEO) have attracted the attention of the scientific community for use in medicinal applications, mainly because of their capacity to incorporate nonsoluble drugs. The hydrophobic nature of the core provides a favorable environment to protect water-insoluble molecules from aggregation and the shell protects sterically against metabolism by biological agents.17,18 Furthermore, temperature strongly influences the pluronic (PLU) micellization process, changing the critical micelle concentration (CMC), aggregation number (Nagg), and particle size. The critical micelle temperature (CMT) is shifted by concentration.19 de Morais et al. improved the hypericin (HYP) photodynamic activity against the trypomastigotes of Trypanosoma cruzi using P123 and F127 in comparison to free HYP or that incorporated in a zwitterionic phospholipid. They observed an EC50 of about 6.1 and 8.5 μmol L−1 when incorporated in F127 and P123 in the absence of light and 0.31−0.36 μmol L−1 in the presence of white light, respectively.20 The photochemical properties of aluminum phthalocyanine chloride (AlPcCl) incorporated in P123 and F127 and its photodynamic inactivation of microorganisms were studied by Vilsinski and co-workers. They observed that the more hydrophobic copolymer P123 presents greater interaction with AlPcCl than does F127. Besides, these bindings were significantly influenced by temperature, given that a rising temperature enhances the interaction between the compound and copolymers. Against Staphylococcus aureus, Escherichia coli, and Candida albicans, they verified that F127 did not show any effect on these microorganisms because of the self-aggregation

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EXPERIMENTAL SECTION Materials. CUR powder (≥65% of CUR) containing a mixture of three major components (CUR, demethoxy curcumin, and bisdemethoxy curcumin), pluronic P123 (PEO20−PPO70−PEO20; 5800 g mol−1), and F127 (PEO100− PPO70−PEO100; 12 600 g mol−1) were purchased from SigmaAldrich (MOUSA). Ethanol, dimethyl sulfoxide, and acetone were obtained from Neon (SPBrazil). All chemicals were used without further purification. Deionized water was used throughout all experiments. Kinetic Evaluation of Diketo/Keto−Enolic Equilibrium. This experiment was carried out based on the studies of Iglesias with some modifications.23 A 50 μL of CUR stock ethanolic solution (0.2 mg mL−1) was transferred to a cuvette containing 2.5 mL of previously thermostated deionized water, vigorously stirred twice for homogenization. The spectra were acquired on a Varian Cary 50 UV−vis spectrophotometer in the range of 290−550 nm for 12 min. The procedure was repeated at six different temperatures (294−314 K) to achieve the activation thermodynamic parameters. The activation energy (Ea) involved in CUR tautomerism was obtained using the Arrhenius equation (eq 1) with the plot of ln(kobs) versus 1/T. kobs = A e−Ea / RT

(1)

where kobs is the CUR tautomeric kinetic constant, R is the gas constant (8.314 J K−1 mol−1), T is the temperature, and A is the Arrhenius pre-exponential factor. The slope is Ea/R. Using the theory of the activated complex, applying eqs 2 and 3, ΔG⧧, ΔH⧧, and ΔS⧧ values can be calculated from the Eyring plot of ln(kobs/T) versus 1/T.24 kobs =

KBT ΔS‡/ R −ΔH ‡/ RT e e h

ΔG‡ = ΔH ‡ − T ΔS‡

(2) (3)

where kobs is the kinetic constant at a given temperature (T), kB is the Boltzmann constant (1.3806 10−23 J K−1), h is the Planck constant (6.626 10−34 J s), ΔH⧧ is the activation enthalpy, ΔS⧧ is the activation entropy, and ΔG⧧ is the Gibbs free energy of activation of the CUR conformational equilibrium process in an aqueous solution. Interaction between CUR and P123 or F127 in an Aqueous Medium. The solubility isotherms of CUR in the copolymers were measured by the fluorimetric titration of aqueous CUR solutions by each PLU stock solution, following the procedure reported by Vilsinski et al.21 The concentration of P123 ranged from 0 to 2.05 mg mL−1, and from 0 to 40.00 mg mL−1 for F127, depending on the evaluated temperature (from 298 to 314 K, with a difference of approximately 4 K between each isotherm). This procedure was applied for four distinct concentrations of CUR stock solutions (0.208, 0.156, 0.104, and 0.052 mg mL−1), adding 10 μL of each stock 5642


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Figure 1. (a) Successive absorbance spectra as a function of time involving the diketo/keto−enolic equilibrium of CUR (3.9 μg mL−1) at 298 K and (b) decay kinetic profile of normalized absorption band with regard to the keto−enol species (428 nm) as a function of temperature.

The system containing CUR was prepared using the solid dispersion method, in which both CUR and PLU were dissolved in ethanol, and then the solvent was evaporated by rotary evaporation (Büchi, R-114) at 50 °C at low pressure. The resultant thin film was kept in a desiccator for 24 h and hydrated using deionized water at 50 °C with the aid of a shaker for 2 h (Scheme S1B).27 The average size of all systems was directly measured through the normalized scattering intensity of the timedependent autocorrelation function. The translational diffusion coefficient D, for particles in translational motion, is obtained from the slope of the relaxation rate Γ versus q2 (Γ = Dq2), where q (eq 8) is the magnitude of the scattering vector at a scattering angle θ for a wavelength λ in the solvent with refractive index n0 (here water).

solution to a cuvette containing 2.0 mL of deionized water. Aliquots of these copolymers were added to the cuvette containing CUR (Scheme S1A). The interaction of CUR with the copolymers was evaluated by acquiring CUR fluorescence spectra in the range of 446−700 nm using λexc = 426 nm and monitoring the increasing fluorescence intensity at 497 nm through a Hitachi F-4500 fluorescence spectrophotometer. The solubility of CUR in the copolymers was obtained by extrapolating two derivative lines (increasing region and saturation region) in each curve of the four CUR stock solutions. The individual intersection of these derivative lines provides the solubility of each quantity of CUR in the copolymer. The slope of the plot of the values of these intersections versus the PLU weight is the solubility (milligram of CUR per gram of PLU). Equation 4 provides the Gibbs free energy. For complex systems, the van’t Hoff equation does not accurately represent the phenomenon. A second-order polynomial equation (eq 5) better describes the thermodynamic behavior of systems such as the solubilization of CUR in PLUs, where the terms a, b, and c are polynomial coefficients.25,26 ΔG = −RT ln(χ )

(4)

ΔG = a + bT + cT 2

(5)

q=

D=

kBT 6πηRH

(9)

where kB is the Boltzmann constant, η is the solvent viscosity, and T is the temperature in kelvin.28 Differential Scanning Calorimetry. Differential scanning calorimetry (DSC) was employed to evaluate the interaction between CUR and each PLU in the solid state. The samples were prepared by solubilizing the different proportions of CUR and P123 or F127 (0−100%) in acetone, and then the resultant solution was allowed to stand overnight for complete solvent evaporation, something similar to Scheme S1B. The interaction between each PLU and CUR was evaluated by melting point depression and/or the disappearance of the melting peak of CUR detected using a Shimadzu DSC-50 differential scanning calorimeter. Next, 5−10 mg of each sample was placed in aluminum pans and subjected to a heating rate of 5 °C min−1 from 0 to 190 °C, under nitrogen atmosphere (50 mL min−1). An empty aluminum pan was used as reference.

∂

i ΔH − ΔG yz zz ΔS = jjj T k {

(8)

The effective hydrodynamic radii (RH) of particles were estimated using the Stokes−Einstein relation (eq 9).

Dividing eq 5 by T and then deriving it in relation to 1/T give the Gibbs−Helmholtz equation (eq 6). Using this equation, it is possible to obtain ΔH at each temperature, by applying the polynomial coefficients a and c, obtained by fitting the experimental data from the plot of ΔG versus 1/T. The entropy value at each temperature was also acquired using eq 7.25

( ΔTG ) = a − cT 2 = 1 ∂( T )

4πn0 iθy senjjj zzz λ k2{

ΔH (6)

(7)

Dynamic Light Scattering. Particle sizes with and without CUR at six different temperatures (294−314 K) were evaluated by dynamic light scattering (DLS) (ALV CGS-3 multi-tau correlator laser goniometer with 35 mW red laser λ = 632.8 nm with temperature control), according to Basak and Bandyopadhyay with few modifications.19 The concentration of both copolymers was 2.5 mg mL−1 and 0.8 μg mL−1 for CUR. All solutions were filtered in a 0.22 μm cellulose acetate filter.

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RESULTS AND DISCUSSION Kinetic Evaluation of Diketo/Keto−Enolic Equilibrium. Two main equilibria can be observed in aqueous media for CUR: aggregation and tautomeric processes.29 However, in low concentrations, the tautomeric equilibrium apparently stands out compared to aggregation if the UV−vis 5643


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The Journal of Physical Chemistry B technique is used to evaluate the process.5 Therefore, UV−vis spectroscopy can be employed to evaluate the kinetics involved in the diketo/keto−enolic equilibrium of CUR in aqueous media. Figure 1 shows the successive spectra of CUR (3.9 μg mL−1) as a function of time because of the change in the solvent (from ethanol to water) and its tautomeric kinetic profile. When an aliquot of CUR ethanol stock solution was transferred to a cuvette containing an aqueous solution, a decay in the keto−enol characteristic band and an increase in the intensity of the diketo band as a function of time were noted, that is, the conformational equilibrium was displaced to the diketo form in aqueous media. The same tendency was noticed by Namazian and co-workers in their theoretical studies.9 The formation of an isosbestic point was also observed near 375 nm during the spectral variation, indicating that the equilibrium process occurs in a single step.5 In this context, it is possible to better understand why the literature presents distinct pKa values for CUR, depending on the method used, especially when measured by spectroscopic methods.30−32 Because the tautomeric equilibrium occurs parallel to the ionic equilibrium, it may be that the spectra obtained by the investigators were acquired before the establishment of the tautomeric equilibrium, and significant disparities of pKa values can be verified. Additionally, studies were carried out to evaluate the influence of temperature on the kinetics related to the CUR tautomeric equilibrium process in aqueous media. The plot showed in Figure 1B exhibits the kinetic profile monitored at 428 nm at different temperatures. It was observed that the rate in which the diketo/keto− enolic equilibrium is established is highly temperaturedependent (Table 1). At 294 K, the equilibrium is reached

when performed at 314 K. Hence, temperature not only influences the displacement of the equilibrium but also the speed with which it occurs. In addition, the decay exponentials fit perfectly to the first-order kinetic model [ln(A − A∞)/(Ao − A∞) vs time] (Figure S1). Activation energy (Ea) was acquired from the kinetic constants as a function of temperature through the Arrhenius plot (Figure S2A) and eq 1. The ΔH⧧ and ΔS⧧ values were obtained using the Eyring plot (Figure S2B) and eq 2. The slope represents ΔH⧧/R, and the term ln(kB/h) + ΔS⧧/R is the intercept. The activation free energy (ΔG⧧) can be obtained from the relationship between ΔH⧧ and ΔS⧧ as a result of eq 3.24 Table 1 shows that kinetic constants (kobs) increase from 7.5 to 35.7 ms−1 as the temperature rises from 294 to 314 K, respectively. The activation energy of the process is approximately 61.2 kJ mol−1, and the values of ΔH⧧ and ΔS⧧ are 58.6 kJ mol−1 and −86.0 J K−1 mol−1, respectively. These values were consistent as the activation enthalpy was positive and the entropy was negative because the entropy of the activated complex must be smaller than the entropy of the reactants and products. Another important piece of information was that both the ΔH⧧ and −TΔS⧧ terms contribute synergistically to the positive value of ΔG⧧. Studies conducted by Chen and colleagues have found a similar Ea for the tautomeric equilibrium of 4-hydroxyphenylpyruvic acid.33 The predominant tautomeric CUR form in the physiological environment can strongly influence the binding of this molecule with cells or specific proteins, as demonstrated by Tooyama and co-workers relative to Alzheimer’s disease.4,34 Interaction between CUR and P123 or F127 in Aqueous Medium. Consequently, it is necessary to find a carrier system which increases the solubility and provides a favorable environment for the maintenance and permanence of CUR in the enol form. PLU copolymers are being used to avoid the dyes drug dimerization (aggregation), thereby enhancing their solubility, stability, and activity in physiological medium. These systems were used to incorporate molecules such as HYP, phthalocyanines, and CUR itself.20,22,35 The copolymeric solution containing PLU may be a versatile route in maintaining CUR tautomeric equilibrium, which is displaced to the enol form in this environment, providing proper characteristics for the good performance of this compound. Nevertheless, the thermodynamics of CUR interaction with those optimal vehicles has scarcely been explored. Figure 2 presents the emission intensity of CUR (2.08 μg mL−1) as a function of PLU concentration at 298 K.

Table 1. Values of Kinetic Constants Related to the Tautomeric Equilibrium of CUR as a Function of Temperature T (K)

kobs (10−3 s−1)

294.15 298.15 302.15 306.15 310.15 314.15

7.46 10.40 15.39 21.13 28.07 35.74

± ± ± ± ± ±

0.05 0.04 0.07 0.11 0.18 0.33

in approximately 700 s, whereas at higher temperatures, kinetics occur more rapidly, being reached in only about 200 s

Figure 2. Fluorescence intensity at 497 nm after successive additions of (a) P123 and (b) F127 in an aqueous solution containing different CUR amounts, at 298 K, with λexc = 426 nm for both PLU copolymers. 5644


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Figure 3. Solubility of each CUR amount at different temperatures to calculate the intrinsic solubility (χ) in (a) P123 and (b) F127.

Table 2. Intrinsic Solubility (χ) and Thermodynamic Parameters Related to the Interaction of CUR with P123 and F127 PLU

T (K)

χ (mgCUR/gPLU)

χ (mmolCUR/molPLU)

ΔG (kJ mol−1)

ΔH (J mol−1)

TΔS (kJ mol−1)

P123

298.15 302.15 306.15 310.15 314.15 298.15 302.15 306.15 310.15 314.15

2.58 5.09 6.28 6.77 6.68 0.05 0.56 1.86 2.75 3.54

40.22 79.45 98.02 105.63 104.30 1.95 19.00 63.56 94.17 121.11

−9.16 −11.02 −11.66 −12.05 −12.13 −1.66 −7.41 −10.57 −11.71 −12.52

119.34 73.75 40.05 −5.81 −34.46 462.59 320.44 203.90 72.11 −68.36

9.28 11.09 11.70 12.05 12.10 2.12 7.73 10.77 11.78 12.45

F127

In aqueous media, the loss of CUR fluorescence emission (Figure S3) occurs because of the quenching process36 caused by water molecules interacting with CUR, capturing its excited energy, and mainly because of self-aggregation.37 The process of individual molecules forming nonfluorescent H-dimers in solution is a phenomenon that originates from a complex equilibrium involving intermolecular forces, where the van der Waals interactions between the molecules of the drug itself (mainly hydrophobic) are more favored in comparison to the drug−water interactions.5,7,37 The addition of consecutive aliquots of the PLU solution favors the increase of CUR emission intensity triggered by the diffusion of CUR to the inner core of the copolymeric micelle, indicating the growth of the monomer-state population associated with an increase in the PLU concentration in the system. These interactions provide a more hydrophobic microenvironment protected from water molecules, preventing or decreasing the CUR quenching and dimerization processes.17,22 In previous studies, it was observed that the micellization process of triblock copolymers formed by the EO and PO groups is accompanied by water elimination from the core.38 Apparently P123 provides a more favorable microenvironment to solubilize CUR, as can be observed in the difference on the X-axis for each copolymer in Figure 2. The CUR−PLU binding isotherms using different CUR amounts (from 0.52 to 2.08 μg; Figure 2) were monitored at a specific emission wavelength (497 nm), presenting an initial simple association step followed by the saturation tendency. The derivative lines were traced in two distinct regions of the curves, and intrinsic solubility (χ) was achieved by the slope of the resultant points. This same experiment was carried out at different temperatures to acquire the intrinsic solubility as a function of temperature (Figure 3) and then to obtain the thermodynamic parameters (ΔH, ΔS, and ΔG) relative to the CUR−PLU interaction.

The distinct solubility of CUR at the same temperature for the copolymers, seen in the X-axis of Figures 2 and 3 summarized in Table 2, is due to the different physicochemical characteristics of each PLU. Although both copolymers have almost the same number of PPO units (∼70), the number of PEO units in F127 is 5 times greater (100) than that in P123 (20), resulting in a hydrophilic−lipophilic balance that is greater for F127 (22) in comparison to P123 (8).39 In this sense, P123 provides a more hydrophobic microenvironment, capable of solubilizing poorly soluble drugs such as CUR better than pluronic F127. According to Hatton et al.40 and Hoffmann et al.,41 triblock copolymers present considerable changes in their micellization process, such as CMC, structural organization, aggregation number (Nagg), hydrodynamic radii, micropolarity, and microviscosity with the solution temperature variation. Therefore, these temperature-dependent parameters are important factors in the interaction between the PLU and hydrophobic drugs. The authors showed that raising the temperature from 298 to 308 K decreases the F127 CMC from 7 to 0.08 and from 0.3 to 0.01 μg mL−1 for P123, whereas Nagg increases from 37 to 82 for F127 and from 86 to 244 for P123. Additionally, they also reported that, at the same temperature, the CMC is greater and the aggregation number of monomeric units necessary to form a stable micelle (Nagg) is smaller for F127 than for P123. Thus, P123 can provide a core richer in PO units.40,41 Table 2 indicates an increase in CUR solubility in PLU micelles associated with the elevation of the solution temperature. A smaller amount of PLU is needed to solubilize a certain quantity of CUR. Raising the temperature from 298 to 314 K, χ increases from 2.58 to 6.68 mg g−1 for P123 and from 0.05 to 3.54 mg g−1 for F127. These values indicate stronger CUR binding with both PLUs at higher temperatures, and the interaction is more favorable with CUR-P123 than with CUR-F127. 5645


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Figure 4. Temperature variation of ΔG related to the binding between CUR and (a) P123 and (b) F127 in aqueous media.

Figure 5. Autocorrelation curves of (a) P123 and (b) F127 (2.5 mg mL−1) formulations containing CUR (0.8 μg mL−1) as a function of temperature. Inset is the plot of Γ vs q2.

coefficients for P123 (a = 1523.8 and c = 0.0158) and F127 (a = 5479.8 and c = 0.0563). Substituting these values into eq 6, ΔH of the CUR solubility process in PLUs at each temperature can be obtained, as shown in Table 2. The entropy value was also obtained by employing eq 7.25 From Table 2, it can be observed that the CUR−PLU interaction process becomes less endothermic (ΔH decreases) with increasing temperature. Entropy follows an opposite tendency compared to enthalpy: it increases when the temperature rises. The contribution of the entropic term (−TΔS) to the interaction spontaneity (ΔG < 0) prevails throughout the studied temperature range. Therefore, the energy required for the CUR incorporation process into the micellar microenvironment becomes smaller with increasing temperature. Dynamic Light Scattering. DLS measurements with 2.5 mg mL−1 PLU solutions, with and without CUR (0.8 μg mL−1), were performed at distinct temperatures within the range of 294−314 K. In these measurements, normalized intensity autocorrelation functions G(τ) were evaluated at 13 scattering angles at each temperature. Figure 5 shows that the relaxation of the correlation function shifts toward shorter times with an increasing temperature for both CUR formulations. Besides, the inset of Figure 5 shows that at the assessed temperatures, G(τ) tends to fit to a single exponential form and Γ tends to vary linearly with q2 at higher temperatures, indicating the diffusive motion of the nearly spherical micelles. By decreasing the temperature to below 298 K for P123 and 302 K for F127, Γ does not vary linearly with q2 and G(τ) no longer tends to fit to a single exponential form. As shown by Basak and Bandyopadhyay, this indirectly establishes that the CMT of PLU lies in the range of 294− 298 K for P123 and 298−302 K for F127, indicating the breakup of the micelles into free unimers in solution.19

This behavior is caused by the CMC decrease and Nagg increase for both PLUs at higher temperatures, followed by the dehydration of polymeric chains, providing a more hydrophobic microenvironment in the inner core of the micelle as well as on the PEO−PPO interface. A higher temperature is the suitable condition to solubilize a larger number of CUR molecules into the micelle core. The discrepancy in the χ value between 298 and 302 K is due to the proximity of the copolymer CMT because it is necessary for F127 unimers to have a higher energy to associate onto micelles and interact with CUR.40,41 Therefore, this method can be very helpful to obtain the solubility value in the polymer solution of compounds obtained (synthesized or extracted) in a small amount and consequently without the possibility of wastage. The van’t Hoff equation is commonly employed to calculate the thermodynamic parameters when ΔH and ΔS are invariable and not temperature-dependent. However, unlike what occurs with ionic surfactants, the process associated with CUR solubility in PLU is very complex because of the PLU micellization path, which is highly temperature-dependent.17,26 In this case, ΔH and ΔS vary with temperature, producing a nonlinear behavior when plotting ln(χ) versus 1/T (Figure S4). Thus, the thermodynamic parameters should be obtained by a more accurate calculation method.42 For a nonlinear temperature dependence of ΔG, a second-order polynomial equation better describes the thermodynamic behavior of the present study.25,26 The ΔH value at each temperature can be acquired through the polynomial coefficients a and c of eq 6, obtained by fitting the experimental data from the plot of ΔG versus T (Figure 4).25 As can be seen in Figure 4, the second-order polynomial fits adequately to the experimental data, providing the polynomial 5646


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Figure 6. DSC curves of pluronic (a) P123 and (b) F127 with an increasing amount of CUR (% w/w) in the solid dispersions. Tamman’s triangle construction showing eutectic melting enthalpy (filled circles) and noneutectic melting enthalpy (open circles) vs the mass percentage of CUR in (c) P123 and (d) F127.

unimers or clusters, once these distributions are found mainly at low temperatures. The other region near 10−20 nm is related to CUR−PLU micelles; these radii are observed predominantly at high temperatures. A third size distribution sometimes can be noted at certain temperatures for some studied systems. This can be associated to the presence of individual unimers in solution. Similar results were observed by Bahadur et al.43 and Sarkar et al.44 Polydispersity for both PLUs also increases substantially when the temperature is lowered and when CUR is incorporated into the micellar core. A broader distribution function indicates higher polydispersity (Figure S5). Basak and Bandyopadhyay also observed that the incorporation of hydrophilic drugs forms larger and more polydisperse micelles, whereas more hydrophobic solutes tend to form smaller and more compact micelles.19 The same tendency was found by Chat et al. in their research involving the incorporation of lavender oil in P123 micelles.45 The nanometric dimensions of CUR-encapsulated micelles favor sterilization, simply by the filtration process, which could be easily delivered to the bloodstream through intravenous injections.19 Differential Scanning Calorimetry. The DSC curves of pure CUR and F127 (Figure S6) obtained at a heating rate of 5 °C min−1 in the temperature range from 0 to 190 °C show only one sharp endothermic event (ΔfusH = 131.0 and 108.3 J g−1, respectively) corresponding to the melting points at 178.4 and 56.4 °C, respectively. P123 presents two broad and small peaks between 0 and 56 °C, indicating that this polymer has double crystallinity, and the major one occurs at 29.7 °C, corresponding with previous research data.46,47 This confirms that under these conditions, the components are stable and do not decompose. Figure 6 shows the DSC curves of various proportions of CUR−PLU with an increasing CUR amount in the system and Tamman’s triangle construction.

The CMT difference for each PLU comes from the distinct PEO block size. F127 has 5 times more EO units than P123, providing a bigger but less compact micelle in comparison to P123. As a consequence, the size obtained through the slope of Γ versus q2 and eq 9 decreases from 32 to 11 nm for P123 and from 101 to 12 nm for F127 when the temperature increases from 294 to 306 K. Basak and Bandyopadhyay verified that when hydrophobic compounds are incorporated in the copolymers, the CMT values decrease because of the presence of these molecules. They noticed that the hydrophobicity of the PPO cores is significantly enhanced, owing to the incorporation of the compounds. This favors micellar aggregation at lower temperatures than those of pure copolymers. In contrast, the average size becomes greater, probably because of the increased spacing between the cores of PPO chains. The authors also verified that the reduction of CMC and CMT are closely related to the incorporated drug partition coefficient, in which an increase in the partition coefficient reduces both CMC and CMT, thereby favoring the formation of micelles at lower concentrations and temperatures.19 However, this behavior was not observed in the present study, which may be because of the concentration difference of copolymers and solutes used in each study. Another possibility is because the change in CMT was weakly displaced relative to the pure PLU solution, hindering its observation in the studied temperature gap. Additionally, Figure S5 shows the apparent radii for the systems containing P123, F127, CUR-P123, and CUR-F127 at different temperatures. It can be observed that only small changes occur in the apparent radii to the samples of pure unloaded P123 or F127 because of the increase of the solution temperature. However, when CUR is incorporated to the formulation, a huge change in radii occurs, presenting at least two distinct size regions. The region with radii higher than 100 nm possibly comprises CUR aggregates associated to PLU 5647


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interaction ranged between −2 and −13 kJ mol−1. Additionally, the DLS measurements displayed an increase in the micelle hydrodynamic radii and polydispersity with the insertion of hydrophobic CUR in the formulation. Melting point depression occurs for both PLU and CUR, indicating that one interferes in the crystalline structure of the other through weak interactions. Eutectic mixtures present a composition of about 15% w/w of CUR for both copolymers. The present investigation showed that both P123 and F127 copolymers could be applied as a suitable matrix to design intravenous formulations of CUR produced by the solid dispersion method, offering a safer and more efficient route of administration.

The analysis of data from Figure 6 clearly indicates that the investigated formulation formed a simple binary eutectic system, in which only two kinds of thermal events are present for the whole range of compositions. The melting points of all pure components (CUR: 178.4, F127: 56.4, and P123: 29.7 °C) were depressed with the eutectic mixture formation by solid dispersion, as shown in the phase diagram in Figure S7. This behavior indicates that one component significantly interferes with the crystalline structure of the other through weak interactions in the nonrandom organized arrangements with higher entropy.48 To evaluate which functional groups are responsible for the CUR interaction with the copolymers, Fourier transform infrared spectroscopy measurements were performed on samples with three CUR−PLU concentration ratios: 25/75, 50/50, and 75/25. However, no conclusive wavenumber shift was observed even in the CUR phenolic hydroxyl or keto− enolic bands (3700−3000 and ∼1700 cm−1, respectively) for all analyzed samples. Nevertheless, the interaction between CUR and PLU actually occurs because of the change of melting points obtained in the DSC studies. We agree with Kee et al. and suggest that the correlations on van der Waals interaction levels could be observed through the NMR spectra of two-dimensional 1H nuclear Overhauser effect spectroscopy.49 Gór niak and colleagues found similar results when evaluating the interaction between imatinib (IMA) and F127 prepared by solid dispersion. They established that the eutectic composition occurs with the mass ratios of 2.3 and 97.7% for IMA and F127, respectively. Below 52.5 °C, the authors reported that both constituents are in the solid state. The first peak near the eutectic composition was formed by solid F127 and liquid IMA < 2.3%. The second peak (the temperature of liquid) was wider, which means the complete melting took place over a temperature range. Above the eutectic composition and temperature, the liquid phase is dependent on the IMA content in the composition.47 The values of the eutectic melting enthalpy (ΔH) obtained by the integration of the eutectic peak area on DSC curves are plotted in Figure 6C,D. These values were determined by Tamman’s triangle construction. The thermal effect of the eutectic transition goes to zero for a composition corresponding to pure CUR, indicating no formation of a terminal solid solution. Near the eutectic point, the DSC curves showed the characteristic overlap of the eutectic and liquidus events in a single peak. The values of the eutectic melting, ΔH (Figure 6, filled circles), increase linearly with the content of P123 and/or F127. For this reason, the eutectic composition was determined by plotting the noneutectic melting enthalpy of CUR as a function of the mass percentage and extrapolating the fitted line to zero enthalpy.47 The eutectic compositions were 15.2 and 14.4 CUR % w/w for P123 and F127, respectively.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpcb.9b04150.

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Experimental methodologies; first-order kinetic linearization involving CUR tautomeric quilibrium as a function of temperature; Arrhenius plot used to obtain Ea and the Eyring plot used to calculate the activation thermodynamic parameters (ΔH‡, ΔS‡, and ΔG‡); graph of ln (χ) versus 1/T usually employed into van’t Hoff equation for P123 and F127; apparent radius acquired at 90° for P123, F127, CUR-P123, and CURF127 systems at different temperatures; and temperature−composition phase diagrams for the CUR-P123 and CUR-F127 eutectic systems (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Phone: +55 48 37214534. ORCID

Alexandre Luis Parize: 0000-0002-9986-1956 Author Contributions

The manuscript was written with the contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Brazilian agencies CAPESfinancial code 001−−and CNPq provided financial support for this research. The authors are thankful to POLISSOL for providing the DLS and fluorimeter equipment and also to LABINC for making the UV−vis technique available.

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ABBREVIATIONS Aβ, amyloid-β; BSA, bovine serum albumin; CMC, critical micelle concentration; CMT, critical micelle temperature; CUR, curcumin; DLS, dynamic light scattering; DMSO, dimethyl sulfoxide; DSC, differential scanning calorimetry; Ea, activation energy; EC50, half-maximal effective concentration; F127, pluronic F127; FTIR, Fourier transform infrared spectroscopy; HLB, hydrophilic−lipophilic balance; HYP, hypericin; IMA, imatinib; NOESY, nuclear Overhauser effect spectroscopy; Nagg, aggregation number; P123, pluronic P123; PEO, poly(ethylene oxide); PLU, pluronic; PPO, poly-

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CONCLUSIONS The present work investigates the CUR tautomerism kinetics and the interaction of this compound with pluronic P123 and F127 in solution and in solid state. The kinetic experiments revealed that the tautomeric equilibrium is displaced to the diketo form with a higher rate as the temperature increases. The fluorimetric method proved the enhancement of CUR solubility in P123 and F127 with increasing temperatures, providing thermodynamic parameters in which ΔG of the 5648


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The Journal of Physical Chemistry B (propylene oxide); χ, intrinsic solubility; λexc, excitation wavelength; λemi, emission wavelength

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(18) Samanta, S.; Roccatano, D. Interaction of Curcumin with PEOPPO-PEO Block Copolymers: A Molecular Dynamics Study. J. Phys. Chem. B 2013, 117, 3250−3257. (19) Basak, R.; Bandyopadhyay, R. Encapsulation of Hydrophobic Drugs in Pluronic F127 Micelles: Effects of Drug Hydrophobicity, Solution Temperature, and PH. Langmuir 2013, 29, 4350−4356. (20) de Morais, F. A. P.; Enumo, A., Jr.; Gonçalves, R. S.; Cesar, G. B.; Miranda, N.; Vilsinski, B. H.; Combuca da Silva, R.; Vataru Nakamura, C.; Hioka, N.; Caetano, W. Hypericin Photodynamic Activity. Part III: In Vitro Evaluation in Different Nanocarriers against Trypomastigotes of Trypanosoma Cruzi. Photochem. Photobiol. Sci. 2019, 18, 487−494. (21) Vilsinski, B. H.; Gerola, A. P.; Lemos, É . O.; Barbosa, P. M.; Campanholi, K. S. S.; César, G. B.; Tessaro, A. L.; Hioka, N.; Caetano, W. Spectroscopic Study of Aluminum Phthalocyanine Chloride (AlPcCl) in Homogeneous and Micro-heterogeneous Media Consisting of P-123 and F-127 Polymeric Micelles. Quim. Nova 2015, 38, 631−639. (22) Vilsinski, B. H.; Gerola, A. P.; Enumo, J. A.; Campanholi, K. D. S. S.; Pereira, P. C. D. S.; Braga, G.; Hioka, N.; Kimura, E.; Tessaro, A. L.; Caetano, W. Formulation of Aluminum Chloride Phthalocyanine in PluronicP-123 and F-127 Block Copolymer Micelles: Photophysical properties and Photodynamic Inactivation of Microorganisms. Photochem. Photobiol. 2015, 91, 518−525. (23) Iglesias, E. Solvent Effects versus Concentration Effects in Determining Rates of Base-Catalyzed Keto-Enol Tautomerization. New J. Chem. 2005, 29, 625. (24) Vanzin, D.; Fiori, S.; França Biondo, P. B.; Feltrim, G.; Gracetto, A. C.; Tessaro, A. L.; Politi, M. J.; Caetano, W.; Hioka, N. Microenvironment Effects on the Kinetics of the Alkaline Hydrolysis of Bispyridinium Conformers. Int. J. Chem. Kinet. 2013, 45, 703−711. (25) De, M.; Bhattacharya, S. C.; Moulik, S. P.; Panda, A. K. Interfacial Composition, Structural and Thermodynamic Parameters of Water/(Surfactant+n-Butanol)/n-Heptane Water-in-Oil Microemulsion Formation in Relation to the Surfactant Chain Length. J. Surfactants Deterg. 2010, 13, 475−484. (26) Ghatak, C.; Rao, V. G.; Mandal, S.; Ghosh, S.; Sarkar, N. An Understanding of the Modulation of Photophysical Properties of Curcumin inside a Micelle Formed by an Ionic Liquid: A New Possibility of Tunable Drug Delivery System. J. Phys. Chem. B 2012, 116, 3369−3379. (27) Li, J.; Wang, X.; Li, C.; Fan, N.; Wang, J.; He, Z.; Sun, J. Viewing Molecular and Interface Interactions of Curcumin Amorphous Solid Dispersions for Comprehending Dissolution Mechanisms. Mol. Pharm. 2017, 14, 2781−2792. (28) Löf, D.; Schillén, K.; Loh, W.; Olofsson, G. A Calorimetry and Light Scattering Study of the Formation and Shape Transition of Mixed Micelles of EO20PO68EO20Triblock Copolymer (P123) and Nonionic Surfactant (C12EO6). J. Phys. Chem. B 2007, 111, 5911− 5920. (29) Bhatia, N. K.; Kishor, S.; Katyal, N.; Gogoi, P.; Narang, P.; Deep, S. Effect of PH and Temperature on Conformational Equilibria and Aggregation Behaviour of Curcumin in Aqueous Binary Mixtures of Ethanol. RSC Adv. 2016, 6, 103275−103288. (30) Bernabé-Pineda, M.; Ramı ́rez-Silva, M. T.; Romero-Romo, M.; González-Vergara, E.; Rojas-Hernández, A. Determination of Acidity Constants of Curcumin in Aqueous Solution and Apparent Rate Constant of Its Decomposition. Spectrochim. Acta, Part A 2004, 60, 1091−1097. (31) Priyadarsini, K. I. Photophysics, photochemistry and photobiology of curcumin: Studies from organic solutions, bio-mimetics and living cells. J. Photochem. Photobiol., C 2009, 10, 81−95. (32) Bharate, S. S.; Kumar, R.; Vishwakarma, R. A. Determining Partition Coefficient (Log P), Distribution Coefficient (Log D) and Ionization Constant (PKa) in Early Drug Discovery. Comb. Chem. High Throughput Screening 2016, 19, 461−469. (33) Huang, Y.; Zhang, X.; Xu, L.; Chen, H.; Chen, G. Characterization of keto-enol tautomerism ofp-hydroxyphenylpyruvic

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Temperature Evaluation of Curcumin Keto-Enolic Kinetics and Its

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