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Langmuir 2009, 25, 3425-3434
Diffusion of an Ionic Drug in Micellar Aqueous Solutions
Huixiang Zhang†,‡ and Onofrio Annunziata*,† Department of Chemistry, Texas Christian UniVersity, Fort Worth, Texas 76129, and Alcon Research Ltd., ReceiVed NoVember 4, 2008. ReVised Manuscript ReceiVed December 18, 2008 Supramolecular carriers such as micelles can be used to noncovalently bind drug molecules for pharmaceutical applications. However, these carriers can fundamentally affect diffusion-based drug transport due to host-guestcoupled diffusion. We report a ternary interdiffusion study on an ionic drug in aqueous micellar solutions. Specifically,high-precision Rayleigh interferometry was used to determine the four multicomponent diffusion coefficients for thepotassium naproxenate-tyloxapol-water ternary system at 25 °C and pH 7. In addition, we have measured drugsolubility as a function of tyloxapol concentration. These measurements were used to characterize drug-surfactantthermodynamic interactions using the two-phase partitioning model. Furthermore, we propose a novel model onhost-guest coupled diffusion that includes counterions. We show that quantitative agreement between model andexperimental diffusion results can be achieved if the effect of micelle solvation on transport parameters is includedin the model. This work represents an essential addition to our previous diffusion study on a nonionic drug and providesguidance for the development of accurate models of drug diffusion-based controlled release in the presence of nanocarriers.
Introduction
corresponding molar fluxes. The four Dij (with i,j ) 1,2) are the Supramolecular systems such as micelles, liposomes, and other ternary diffusion coefficients. Main-diffusion coefficients, D11 nanoparticles are valuable tools in the chemical and pharma- and D22, describe the flux of a solute due to its own concentration ceutical fields because they can be used to reversibly bind drug gradient, while cross-diffusion coefficients, D12 and D21, are compounds, thereby enabling controlled release and targeted responsible for the flux of a solute due to the concentration gradient delivery. They also reduce toxicity, enhance bioavailability, and improve stability of therapeutic agents.1-3 Several inter-diffusion studies have been reported in relation Inter-diffusion (or mutual-diffusion) coefficients of drug com- to host-guest systems forming 1:1 complexes. The most relevant pounds are crucial parameters used for modeling, predicting, and cases involve binding of small molecules to cyclodextrines.10,11 designing drug release from delivery devices (gels or other porous One important aspect of these investigations is the observation materials) and other processes such as transport across mem- of large negative values of the cross-diffusion coefficient branes.4-8 However, in the presence of supramolecular systems, responsible for the flux of guest molecules from low to high drug diffusion becomes coupled to that of the hosting particle.9-13 cyclodextrine concentration.15-17 However, in many cases, host The description of drug-host diffusion transport in solution particles may bind more than one guest molecule.3 The most requires the use of Fick’s first law extended to ternary systems:14 common example is represented by micellar systems.1 Clearly,diffusion studies on these systems represent an essential addition -J ) D C + D C to those performed on 1:1 host-guest complexes.
We note that accurate self-diffusion coefficients for drug and J ) D C + D C surfactant molecules in solution have been obtained by pulsed- gradient spin-echo NMR (PGSE-NMR). The dependence of 1 and C2 are the molar concentrations of the two solutes, drug(1) and host system(2), respectively, and J self-diffusion coefficients on system composition has been used to determine micellization parameters and drug-micelle bind- * Corresponding author. Phone: (817) 257-6215. Fax: (817) 257-5851.
ing.18-21 However, self-diffusion coefficients cannot generally replace inter-diffusion coefficients when describing transport processes in the presence of concentration gradients. This is especially true when considering ionic species and chemical (1) Malmsten, M. Surfactants and Polymers in Drug DeliVery; Marcel Dekker: association.22,23 Furthermore, self-diffusion studies on multi- (2) Batrakova, E. V.; Kabanov, A. V. J. Controlled Release 2008, 130, 98–
(3) Li, C.; Wallace, S. AdV. Drug DeliVery ReV. 2008, 60, 886–898.
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3426 Langmuir, Vol. 25, No. 6, 2009 component systems yield no information on cross-diffusion in targeting and controlled-release applications because drug binding strength to the host particle can be tuned by physico- Several interdiffusion studies have been reported on surfactant chemical changes of their surrounding environment.35,36 Hence, multicomponent systems.9,24-28 These investigations have mainly investigating diffusion of an ionic drug in the presence of micelles focused on the formation of mixed micelles in aqueous represents an essential addition to our previous diffusion study solutions.24-26 In relation to micellar solubilization, few studies have been reported on aqueous solutions of n-alcohols and sodium We report measurements of the four diffusion coefficients dodecylsulfate.27,28 In relation to drug compounds, we have for the naproxen-tyloxapol-water ternary system at 25 °C recently reported a diffusion study on drug molecules in micellar and pH 7.3 by Rayleigh interferometry. Naproxen (S(+)- aqueous solutions.9 Specifically, using Rayleigh interferometry, 2-(6-methoxy-2-naphthyl) propionic acid, pK ) we have determined the four diffusion coefficients for the nonsteroidal anti-inflammatory drug with analgesic and hydrocortisone-tyloxapol-water ternary system at 25 °C, where antipyretic properties.36-39 At the experimental pH, naproxen hydrocortisone is a nonionic drug and tyloxapol is a nonionic exists predominantly in its anionic form. In our investigation, the drug is a potassium salt. We include solubility measurements Tyloxapol, which is a commercially available surfactant at a for potassium naproxenate as a function of tyloxapol concentra- relatively low cost, is essentially an oligomer of octoxynol 9 tion. We then introduce a novel model on host-guest coupled (Triton X-100) mostly used in marketed ophthalmic products diffusion that includes counterion effects. We show that and as a mucolytic agent for treating pulmonary diseases.29-32 quantitative agreement can be obtained between model and Tyloxapol has a critical micellar concentration (cmc) of 0.038 behavior of the four experimental diffusion coefficients if the g/L in water at 25 °C.29 This cmc value is much lower than that effect of micelle hydration is taken into account.
of Triton X-100. Hence, the presence of free surfactant can be Materials and Methods
neglected with respect to micellar surfactant for concentrationsof the order of 1 g/L or higher. We note that tyloxapol micelles Materials. Naproxen was purchased from TCI America (Portland,
are spherical with a diameter of 7 nm, and their size and shape OR). Potassium hydroxide and tyloxapol (SigmaUltra grade) were do not change significantly for concentration as high as 10% by purchased from Sigma Chemical Co. (St. Louis, MO). Glacial aceticacid and acetonitrile were purchased from EMScience and EMD weight according to cryo-transmission electron microscopy.30 Chemicals Inc. (Gibbstown, NJ), respectively. Materials were used We also point out that tyloxapol hydrophilic groups are as received from the manufacturers. The molecular weights for poly(ethylene glycol) chains, a chemical motif often encountered naproxen and tyloxapol were taken to be 230.26 and 4500 g mol-1, in supramolecular systems of pharmaceutical relevance.33 All of respectively. Deionized water was passed through a four-stage these features make tyloxapol micelles a model supramolecular Millipore filter system to provide high-purity water for all of the system for host-guest physicochemical studies relevant to experiments. Stock solutions of tyloxapol-water and naproxen-water were made by weight to 0.1 mg. To prepare potassium naproxenate, For the previously investigated hydrocortisone-tyloxapol-water the pH of the naproxen stock solution was increased to pH ≈ 7 using system, the determined diffusion coefficients were examined KOH. Precise masses of stock solutions were added to flasks anddiluted with pure water to reach the final target concentrations of using a drug-micelle coupled-diffusion model based on drug the solutions used for the diffusion experiments. All final solutions partitioning between the aqueous and micellar pseudophases.
used for diffusion and solubility measurements displayed pH values Drug partitioning was characterized by measuring the solubility within the range 7.3 ( 0.3. At these pH values, the neutral form of of hydrocortisone as a function of tyloxapol concentration. A naproxen has a concentration of 0.1% or lower based on pK ) quantitative agreement between the experimental behavior of drug diffusion coefficients, D11 and D12, and a model based on Density Measurements. Molar concentrations of the solutions
dependence of drug solubility on surfactant concentration was were obtained from density. All density measurements were made obtained. One important result of this investigation is that at 25.00 °C with a computer-interfaced Mettler-Paar DMA40 density hydrocortisone diffusion is not only modulated by its binding to meter, thermostatted with water from a large, well-regulated ((1 the slowly diffusing micelles but also because of the presence Solubility Measurements. Solid naproxen compound was added
in excess to tyloxapol-water solutions in glass vials, and pH was In this article, we extend our interdiffusion studies to the case adjusted to pH 7.3 using KOH. The obtained heterogeneous samples of ionic drugs. Drugs with ionic structure are frequently were continuously agitated for 10 days in a regulated water bath at encountered in pharmaceutical applications.34 Furthermore, they 25.0 ( 0.1 °C. Aliquots of the suspensions were then passed through can be also generated from nonionic drugs in situ by a pH change 0.2 µm filters (Millipore) and, if necessary, diluted with the HLPC under physiological conditions. This feature is very important mobile phase (see below) so that the final drug concentration wasaround 0.1 mg/mL. The drug concentration of the properly dilutedsamples was then measured using HPLC (Waters Alliance 2695) (23) Annunziata, O.; D’Errico, G.; Ortona, O.; Paduano, L.; Vitagliano, V. J. Colloid Interface Sci. 1999, 216, 16–24.
equipped with a UV detector (Waters model 2487). A Waters (24) Halvorsen, H. C.; Leaist, D. G. Phys. Chem. Chem. Phys. 2004, 6, 3515–
Symmetry C18 column (size: 4.6 150 mm) was employed with a mobile phase consisting of a 39.7/59.5/0.008 (v/v/v) mixture of (25) Leaist, D. G.; MacEwan, K. J. Phys. Chem. B 2001, 105, 690–695.
acetonitrile/water/glacial acetic acid with a flow rate of 1.2 mL/min.
(26) Castaldi, M.; Constatino, L.; Ortona, O.; Paduano, L.; Vitagliano, V.
Langmuir 1998, 14, 5994–5998.
Chromatograms were obtained at 254 nm.
(27) Leaist, D. G. Can. J. Chem. 1990, 68, 33–35.
Rayleigh Interferometry. Diffusion measurements on naproxen
(28) Leaist, D. G.; Hao, L. J. Chem. Soc., Faraday Trans. 1995, 91, 2837–
(1)-tyloxapol(2)-water(0) ternary systems and corresponding binary aqueous systems were made with the high-precision Gosting (29) Scott, H. J. Colloid Interface Sci. 1998, 205, 496–502.
(30) Regev, O.; Zana, R. J. Colloid Interface Sci. 1999, 210, 8–17.
(31) Westesen, K. Int. J. Pharm. 1994, 102, 91–100.
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(32) Westesen, K.; Koch, M. H. J. Int. J. Pharm. 1994, 103, 225–236.
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(33) Jain, A.; Jain, S. K. Crit. ReV. Ther. Drug Carrier Syst. 2008, 25, 403–
(37) Fini, A.; Fazio, G.; Feroci, G. Int. J. Pharm. 1995, 126, 95–102.
(38) Cirri, M.; Maestrelli, F.; Corti, G.; Furlanetto, S.; Mura, P. J. Pharm. (34) Stahl, P. H., Wermuth, C. G., Eds. Handbook of Pharmaceutical Salts: Biomed. Anal. 2006, 42, 126–131.
Properties, Selection, and Use; Verlag Helvetica Chimica Acta: Zu¨rich, 2002.
(39) Chowhan, Z. T. J. Pharm. Sci. 1978, 67, 1257–1260.
Diffusion of an Ionic Drug in Micellar Aqueous Solutions Langmuir, Vol. 25, No. 6, 2009 3427 where K is the partitioning constant, C(M) molar concentrations in the micellar and water pseudophases,respectively, and CD is the free drug molar concentration in thetotal volume. We note that C(W) in pure water. Drug solubility, S1, is the sum of two contributions:C ) 0 S1(1 - φ) (free drug) and CD φ ) K S1φ (bound drug).
We therefore obtain the following linear relation:9 S ) S0[1 + (K - 1)φ] We note that eq 3 applies to both neutral and ionic drugs and Figure 1. Solubility of naproxen in tyloxapol-water mixtures as a
electroneutrality is not assumed to hold for the pseudophases.
function of tyloxapol volume fraction at 25 °C and pH 7. The solid curve We fit our solubility data to eq 3 and obtain: S0 ) is a linear fit through the data using eq 3.
and K ) 25 ( 1 at 25 °C and pH 7.3. The obtained value of Kwill be used to compare the experimental diffusion results with diffusiometer operated in its Rayleigh interferometric mode.14,40-43 A comprehensive description of the Gosting diffusiometer can be Ternary Diffusion Coefficients. The interdiffusion coefficients
found in ref 43 and references therein.
Diffusion experiments were accomplished by setting up a sharp in eqs 1a,b can be described relative to different reference horizontal interface (free boundary) between a bottom and a top frames.48 Diffusion measurements yield, to an excellent ap- solution with different composition in a vertical diffusion channel.
proximation, diffusion coefficients relative to the volume-fixed A necessary condition for eliminating convection is that the fluid frame. Here, the fluxes of the components of a ternary system density must decrease from bottom to top along the diffusion channel at any point during the experiment.44 For each ternary solution “2”, and “0” denotes the drug, surfactant, and solvent components, composition, at least four diffusion experiments were performed at respectively, and the subscript “V” appended outside the virtually the same average concentration of naproxen, C1, and parentheses identifies the volume-fixed frame. Hence, the tyloxapol, C2. To obtain the four diffusion coefficients, experiments measured diffusion coefficients will be denoted as (D must be performed with different values of the ratio ∆CC2), where ∆Ci is the difference in concentration of solute i betweenthe bottom and top sides of the initial diffusion boundary. Details The four interdiffusion coefficients for the naproxen- on the method and individual diffusion experiments are given as tyloxapol-water ternary system were determined as a function Supporting Information. We note that experiments with ∆C of tyloxapol concentration at 25 °C and pH 7.3. The naproxen concentration was kept constant at C ) 6 mM. Our results are 2) ≈ 1 displayed double-diffusive convection due to dynamic gravitational instability,44-46 which arises at the interface (see Supporting Information). Hence, the experiments used for the 0 in Figure 2a is the diffusion coefficient, (D1)V, for the determination of ternary diffusion coefficients were performed away drug-water binary system. At infinite dilution, (D where D( is the mean-ionic tracer diffusion coefficient. Thiscoefficient is related to the tracer diffusion coefficients of the naproxenate anion, DD, and the potassium cation, DK, through Drug Solubility. Figure 1 shows solubility of potassium
the Nernst-Hartley equation: D( ) 2DDDK/(DD our experimental drug concentration is low, the obtained diffusion 1, as a function of volume fraction, φ, of tyloxapol(2) at 25 °C and pH 7.3. Surfactant volume fractions value can be assumed to be equal to D(. Because DK is the tyloxapol partial molar volume.9 Drug solubility, S Nernst-Hartley equation. Comparison between DD and (D1)V shows that diffusion of ionic drugs can be significantly faster φ within the experimental error up to surfactant volume fractions as high as 0.10. This result demonstrates that than that predicted from its tracer diffusion value. In other words, naproxenate anions bind to tyloxapol micelles. Binding can be counterion diffusion generates an electrostatic dragging effect quantitatively characterized by employing a two-phase partition- ing model.35,47 Within this model, drug molecules are assumed The drug main-diffusion coefficient (D11)V in Figure 2a to partition between the micelle-free aqueous pseudophase (free decreases as the surfactant concentration increases. This behavior, drug) and the micellar pseudophase (bound drug). This partition- which can be related to the formation of drug-micelle com- ing equilibrium is described by the following ideal-dilute plexes,9 is qualitatively consistent with our solubility results.
The relation between (D11)V and K for the case of ionic drugswill be given in the following section.
In Figure 2b, we show the surfactant main-diffusion coefficient, (40) Miller, D. G.; Albright; J. G. In Measurement of the Transport Properties of Fluids: Experimental Thermodynamics; Wakeham, W. A., Nagashima, A., (D22)V. For comparison, we include the corresponding surfactant Sengers, J. V., Eds.; Blackwell Scientific Publications: Oxford, 1991; Vol. 3, pp binary values, (D2)V (dashed curve).9 We can see that (D2)V slightly (41) Annunziata, O.; Buzatu, D.; Albright, J. G. Langmuir 2005, 21, 12085–
increases with increasing surfactant concentration. This behavior can be attributed to steric repulsive interactions between micelles.9 (42) Zhang, H.; Annunziata, O. J. Phys. Chem. B 2008, 112, 3633–3643.
The ternary values have been found to be 5-8% higher than the (43) Albright, J. G.; Annunziata, O.; Miller, D. G.; Paduano, L.; Pearlstein, A. J. J. Am. Chem. Soc. 1999, 121, 3256–3266.
(44) Miller, D. G.; Vitagliano, V. J. Phys. Chem. 1986, 90, 1706–1717.
(48) Kirkwood, J. G.; Baldwin, R. L.; Dunlop, P. J.; Gosting, L. J.; Kegeles, (45) Huppert, E. H.; Hallworth, M. A. J. Phys. Chem. 1984, 88, 2902–2905.
G. J. Chem. Phys. 1960, 33, 1505–1513.
(46) Vitagliano, V. Pure Appl. Chem. 1991, 63, 1441–1448.
(49) Robinson, R. A.; Stokes, R. H. Electrolyte Solutions; Academic Press: (47) Stilbs, P. J. Colloid Interface Sci. 1982, 87, 385–394.
3428 Langmuir, Vol. 25, No. 6, 2009 Figure 2. Ternary interdiffusion coefficients for the naproxen(1)-tyloxapol(2)-water system as a function of tyloxapol volume fraction at 25 °C
and pH 7.3. (A) Naproxen main-diffusion coefficient (D11)V. (B) Tyloxapol main-diffusion coefficient (D22)V; the dashed curve represents the corresponding
binary interdiffusion coefficients for the tyloxapol-water system calculated using (D
DM (1 + 17.13 φ) / (1 + 14.34 φ), where DM × 10-9 m2 s-1 is the tracer diffusion coefficient of tyloxapol micelles in water. Binary diffusion data are reported in ref 9. (C) Naproxen cross-diffusioncoefficient (D12)V. (D) Tyloxapol cross-diffusion coefficient (D21)V. Solid curves are weighted fits through the data.
corresponding binary ones. This change, which has not been counterions. Hence, a net diffusion of surfactant component occurs observed in the case of the hydrocortisone-tyloxapol-water from high to low drug concentration. We will discuss this system, can be related to a drug-induced charge on the micelles electrostatic effect in the following section.
and counterions. We will discuss this electrostatic effect in thefollowing section.
Diffusion Model
The drug cross-diffusion coefficient (D12)V in Figure 2c is negative. This result has been obtained also in the case of the General Diffusion Equations. Multicomponent interdiffusion
hydrocortisone-tyloxapol-water system, and it has been gener- coefficients, Dij, are combinations of thermodynamic factors and ally observed for host-guest systems. A direct comparison fundamental transport coefficients. Hence, to obtain theoretical between the hydrocortisone and naproxen systems can be expressions for Dij, we need to model both thermodynamic and performed by considering the ratio (D transport properties of the system. Although diffusion coefficients 12)V/C1, because Dij (with i * j) is directly proportional to C are obtained in the volume-fixed frame, the relation of diffusion i.14 We find that (D12)V/C1 ranges from -3 to -4 × 10-8 m2 s-1 M-1 for the naproxen case to thermodynamics is simpler in the solvent-fixed frame for which and from -3 to -7 × 10-8 m2 s-1 M-1 for the hydrocortisone 0.50-52 Here, the subscript “0” appended outside the case9 in the same range of tyloxapol concentrations. Thus, the parentheses identifies the solvent-fixed frame. The corresponding two sets values have similar magnitude. The negative sign of diffusion coefficients will be denoted as (Dij)0 (with i,j ) 1,2).
The theoretical (Dij)V values can be calculated from the 12)V can be understood by considering a concentration gradient of micelles in the presence of a uniform concentration of the corresponding (Dij)0, provided that the Vi are known.
drug component. In these conditions, the concentration of free According to nonequilibrium thermodynamics, diffusion for drug molecules increases from high to low micelle concentration.
a ternary system can be described using the following linear The resulting gradient will induce drug diffusion from low to high micelle concentration on a time scale shorter than thatrequired for dissipating the concentration gradient of the slowly -(J ) ) (L ) ∇ µ + (L ) ∇ µ diffusing micelles. As in the case of (D11)V, we will discuss the -(J ) ) (L ) ∇ µ + (L ) ∇ µ 12)V to the partitioning constant, K, in the following where µi is the chemical potential of the ith component, and (Lij)0 The surfactant cross-diffusion coefficient (D21)V in Figure 2d are the solvent-frame Onsager transport coefficients. These significantly increases with C2. The positive value of (D21)V/C2 coefficients satisfy the Onsager reciprocal relation (ORR): (L12)0 can be attributed to a drug-induced charge on the micelles andcan be understood by considering a concentration gradient of (50) Miller, D. G.; Vitagliano, V.; Sartorio, R. J. Phys. Chem. 1986, 90, 1509–
drug component in the presence of a uniform concentration of (51) Dunlop, P. J.; Gosting, L. J. J. Phys. Chem. 1959, 63, 86–93.
micelles. In these conditions, both free drug and micelle-drug (52) Woolf, L. A.; Miller, D. G.; Gosting, L. J. J. Am. Chem. Soc. 1962, 84,
complexes will be electrostatically dragged by the faster potassium Diffusion of an Ionic Drug in Micellar Aqueous Solutions Langmuir, Vol. 25, No. 6, 2009 3429 ) (L21)0.53,54 We can use eqs 1a,b and 4a,b to relate the solvent- be used to calculate the average number of drug species, 〈i〉, and fixed diffusion coefficients and Onsager transport coefficients counterions, 〈j〉, bound to each micelle by: (D ) ) (L ) µ + (L ) µ (D ) ) (L ) µ + (L ) µ (C /m) 1 + (K - 1)φ (D ) ) (L ) µ + (L ) µ (D ) ) (L ) µ + (L ) µ ij ≡ (∂µi/∂Cj)T,p,C k,k*j, T is the temperature, and p is the (C /m) 1 + (- 1)φ pressure.50-54 We will now derive expressions for the thermo- ij, and the Onsager coefficients (Lij)0.
Thermodynamic Factors. We consider a drug(1)-surfactant
To obtain expressions for the four thermodynamic factors in eqs (2)-water(0) ternary system at constant temperature. The drug 5a-d, the following chemical-potential expressions are hypoth- component is ionic, and the surfactant component is neutral. The composition of this system is characterized by the drug andsurfactant molar concentrations, C1 and C2, respectively. We µ ) µ0 + RT ln C(W) + RT ln C(W) neglect the concentration of the free surfactant because the tyloxapol cmc is significantly lower than our experimental C ) + RT ln C + RT ln y(φ) values. Micelles are assumed to be monodisperse with aggregation number, m, and molar concentration, C where µ and µ are the standard chemical potentials, C Solubilization of ionic drug molecules into micelles is related molar concentration of the free micelles (MDiKj with i ) j ) to the formation of a wide range of micelle-drug complexes and 0), and R is the ideal-gas constant. Equation 9a is consistent with generally includes counterion binding. We will denote the generic the two-phase partitioning model. On the other hand, eq 9b is an addition to the two-phase model and characterizes the iKj, where M, D, and K identify micelle, drug, and counterion, respectively. For anionic drugs, micellar translational entropy of the micelles, which is the driving force complexes display a net charge equal to j - i. Concentrations for their diffusion. The micelle activity coefficient, y(φ), describing of individual species are related to the component concentrations the deviation from ideal-dilute solution, is assumed to be not The free micelle concentration in eq 9b cannot be directly determined from the two-phase partitioning model. Its deter- mination requires knowledge of the distribution function, f(i,j),of the MD iKj species so that CMD f(i,j) (C2/m). However, if drug-micelle binding is assumed to be independent of i + j, we can assume that f(i,j) is given by the bivariate Poisson distribution where CD, CK, and CMD function f(i,j) ) (e-〈i+j〉/(i + j)!)〈i + j〉(i+j).55 For this special case, drug, free counterion, and drug-micelle complexes, respectively.
CM can be determined provided that 〈i〉 and 〈j〉 are known: These concentrations can be determined if the equilibrium constants for the formation the drug-micelle complexes are C ) f(0, 0)(C /m) ) e ie j〉(C /m) known. This complicated chemical-equilibrium problem can be simplified using the two-phase partitioning model19,47 based on The concentrations CD and CK in eq 9a can be related to C1 eq 2. To take into account binding of counterions to micelles, using eqs 2 and 7, while the concentration CM in eq 9b can be we also introduce the following partitioning equilibrium condition: related to C2 using eqs 8a,b and 10. We can therefore rewrite theexpressions of the solute chemical potentials in the following where τ is the drug-counterion partitioning constant, and C(M) are the counterion molar concentrations in the micellar and water pseudophases, respectively. The value of τ ) 0 (µ - µ )/RT ) 1 ln corresponds to the case of no counterion binding to micelles. On the other hand, the value of τ ) 1 corresponds to the case of counterion and drug binding strengths to micelles being identical.
In this latter case, the net micelle charge is zero. It can be easily Expressions for the thermodynamic factors are then extracted shown that the product represents the partitioning constant for the counterions between the aqueous and micellar pseudophases.
We note that counterion binding is likely to occur within the hydrophilic domain of the micelles. Because the volume of themicellar hydrophilic domain is directly proportional to the total C (µ /RT) ) -φ partitioning remains valid. Because K and τ are related to CD and C (µ /RT) ) -φ( K (see eqs 2 and 7), the values of these binding constants can (53) Onsager, L. Phys. ReV. 1931, 38, 2265–2279.
(55) Brownlee, K. A. Statistical Theory and Methodology in Science and (54) Miller, D. G. J. Phys. Chem. 1959, 63, 570–578.
Engineering, 2nd ed.; John Wiley & Sons: New York, 1965.
3430 Langmuir, Vol. 25, No. 6, 2009 the resulting expressions into eqs 14a,b, we obtain two equations + [ K(K-1)φ2 + (-1)φ2 ]C1 that can be directly compared to eqs 4a,b. This comparison allows (1 - φ + Kτφ)2 C2 us to obtain the following expressions for the (L ≡ 1 + (d ln y/d ln C2) is the thermodynamic factor of (L ) ) (L ) - 2C [(ν/m)V low surfactant concentrations. We observe that the expression of µ21 based on the Poisson distribution is equal to (1 - φ) µ12 [1 - C [(ν/m)V 1/C2) µ11. This result could be also derived from the thermodynamic relation between the four µ ) 0.9,54 This is consistent with the two-phase partitioning model, which assumes that drug molecules do not affect the volume of [1 - C (ν/m)V both pseudophases. This approximation is reasonable at low drug We will now derive expressions for the (L (1) the free-solvent fluxes of individual solvated species in solution Onsager Transport Coefficients. The determination of the
are uncoupled, (2) the diffusion coefficient of each species is solvent-frame Onsager transport coefficients, (Lij)0, requires the constant and equal to the corresponding tracer diffusion coefficient identification of the actual diffusing species in solution. Typically in water, and (3) the diffusion coefficient of the micelle-drug coupled diffusion between these species is assumed to be complexes is equal to that of the free micelles. We can therefore negligible, and models are then constructed to obtain expressions Recently, it has been experimentally observed that the solvent- -J ) C D µ˜ /RT 12)0 is negative for poly(ethylene glycol), a hydrophilic macromolecule, in aqueous salt solutions.56 This -J ) C D µ˜ /RT result can be explained by considering the role of solute solvation.
Indeed, the actual diffusing solute species are solvated, and their /RT with i, j ) 0, 1, 2, .
diffusion behavior should be described with respect to the free- solvent reference frame, where (J0ˆ)0ˆ ) 0 with the subscript “0ˆ”denoting the free solvent.57 Because surfactants with polyethylene where DD, DK, and DM are the tracer diffusion coefficients of free oxide head groups are significantly hydrated, we will include the drug anion, free counterion, and micelle complexes, respectively.
effect of micelle solvation in our model.
In eqs 17a-c, JD, JK, and JMD are the free-solvent frame fluxes The actual thermodynamic driving forces for diffusion of the individual species (where we have omitted frame notation described in the free-solvent reference frame are the chemical for simplicity), and µ˜D, µ˜K, and µ˜MD potentials for hydrated solutes, µˆ binding, the chemical potential of the hydrated surfactant is µˆ2 To determine the relations between the (Lij)0ˆ and the tracer (ν/m) µ0, where ν is the number of solvent molecules diffusion coefficients, we need to link the fluxes and the bound to the micelle and µ0 is the water chemical potential. We electrochemical-potential gradients of the species to the fluxes shall neglect the contribution of drug and counterion hydration and the chemical-potential gradients of the components. Fluxes because (1) it is expected to be significantly smaller than that of individual species are linked to those of the components through of the micelles and (2) it considerably increases the number of the following mass balances based on eqs 6a,b: variables because the hydration state of these species will changeupon binding to the micelles. We will therefore set µˆ ) (J ) ) J + ∑ ∑ iJ Linear laws in the free-solvent reference frame are:57 where (Lij)0ˆ are the corresponding Onsager transport coefficients Electroneutrality and chemical-equilibrium conditions allow us that satisfy the ORR: (L12)0ˆ ) (L21)0ˆ. The relation of (Lij)0 to (Lij)0ˆ can be obtained by considering the following relations for the results can be extended to the corresponding gradients: (J ) ) (J ) - C [(ν/m)Vµ˜ + ∇ µ˜ ) ∇ µˆ (J ) ) [1 - C (ν/m)V m µˆ with i, j ) 0, 1, 2, .
(Ji)0ˆ - (Ci/C0)(J0)0ˆ, and the following relations for the chemical-potential gradients: If we insert eqs 17a-c and eq 19b into eq 18a, we obtain an equation that relates ∇µ˜D and ∇µ˜K to ∇µˆ2. This equation together with eq 19a allows us to obtain the following expressions for ˆ ) [1 - C (ν/m)V where we have applied the Gibbs-Duhem equation to elimi- nate ∇µ0. By inserting eqs 15a,b into eqs 13a,b and then inserting [C D + (C /m)D (〈j2 〉 -〈ij 〉 )] ∇ µˆ - C D (〈i 〉 -〈j 〉 ) ∇ µˆ (56) Tan, C.; Albright, J. G.; Annunziata, O. J. Phys. Chem. B 2008, 112,
[C D + C D + (C /m)D (〈i2 〉 + 〈j2 〉 -2〈ij 〉 )] (57) Annunziata, O. J. Phys. Chem. B 2008, 112, 11968–11975.
Diffusion of an Ionic Drug in Micellar Aqueous Solutions Langmuir, Vol. 25, No. 6, 2009 3431 [C D + (C /m)D (〈i2 〉 -〈ij 〉 )] ∇ µˆ - C D (〈j 〉 -〈i 〉 ) ∇ µˆ 2(1 - φ)2D D + 2[(1 - φ)(τD + D ) + KτφD ]D (1 - φ){[1 + (- 1)φ]D + [1 + (K - 1)φ]D } + [(1 + τ)(1 - φ) + 2Kτφ]D [C D + C D + (C /m)D (〈i2 〉 + 〈j2 〉 -2〈ij 〉 )] In the case of nonionic drugs, eq 25 reduces to (D where we have used the definition 〈x〉 ≡ ∑ j ) 0 x f(i,j). The M]/(1 - φ + ) is the self- corresponding expression for ∇µ˜ diffusion coefficient of the nonionic drug in the presence of eqs 20a,b into eq 19b. We are now in position to obtain expressions ˜ D is a weighed average between DD and for the (Ji)0ˆ (with i ) 1,2) as a function of the ∇µˆi. Comparison DM. We can also consider eq 25 in the limiting case of τ ) 0 with eqs 13a,b yield the following expressions for the (Lij)0ˆ: (no counterions binding). In this case, we obtain the Nernst-Hartleyequation: (D C D C D + (C /m)D [C D j2 〉 + C D i2 〉 + (C /m)D (〈i2 〉 〈j2 〉 -〈ij〉2)] counterions, we conclude that (D11)V RT[C D + C D + (C /m)D (〈i2 〉 + 〈j2 〉 -2〈ij 〉 )] counterions exert an electrostatic dragging effect on the slower drug ions to preserve electroneutrality. Finally, we note that mand ν have no effect on (D11)V in this limit.
To examine the other three interdiffusion coefficients, we shall C D j 〉 + C D i 〉 + (C /m)D [〈i 〉 (〈j2 〉 -〈ij 〉 ) + 〈j 〉 (〈i2 〉 -〈ij 〉 )] consider the limit of infinite dilution with respect to both C RT[C D + C D + (C /m)D (〈i2 〉 + 〈j2 〉 -2〈ij 〉 )] 2. In the case of (D12)V, we obtain: 12 V ) -D([K(1 + τ) - 2] + C D + C D + (C /m)D [〈i2 〉 -〈i〉2 + 〈j2 〉 -〈j〉2 - 2(〈ij 〉 -〈i 〉 〈j 〉 )] RT[C D + C D + (C /m)D (〈i2 〉 + 〈j2 〉 -2〈ij 〉 )] The values of 〈i〉 and 〈j〉 can be determined from eqs 8a,b providedthat K and τ are known. However, the determination of 〈i2〉, 〈j2〉, In eq 26, the second term contributes marginally to the value of and 〈ij〉 requires a further assumption on f(i,j). Although the (D12)V/C1, because DM is small as compared to D( ) 2DDDK/(DD values of 〈i〉 and 〈j〉 are related to each other, we can assume that + DK). Indeed, we can approximately write: (D12)V/C1 ≈ -D( j - 〈j〉 for the counterion does not correlate with i - 〈i〉 for the V2 K(1 + τ), where we have also assumed that K . 2. We conclude drug. Within this assumption, f(i,j) becomes the product of two that also this coefficient is not very sensitive to the values of m independent Poisson distribution functions:55 and ν. This cross-term is predicted to be negative and directly proportional to K for both ionic and nonionic drugs. In other 〈i + j〉(i+j) ) (e ii words, due to drug-micelle binding, a concentration gradient of micelle induces a flux of drug component from low to high Using the mathematical properties of independent Poisson micelle concentration. Our experimental results on both potassium distribution functions, we can determine 〈i2〉, 〈j2〉, and 〈ij〉 from naproxenate and hydrocortisone are in agreement with the 〈i〉 and 〈j〉 according to: 〈i2 〉 ) 〈i 〉 + 〈i〉2 The limiting expression of (D21)V is 〈j2 〉 ) 〈j 〉 + 〈j〉2 〈ij 〉 ) 〈i 〉 〈jDiffusion Coefficients. The values of (L
ij)0 and µij/RT can be determined provided that K, τ, m, ν, D D, DK, and DM are known.
We can then calculate (Dij)0 using eqs 5a-d. Finally, the (Dij)0can be converted into (D ij)V using previously reported equations 21)V/φ is directly proportional to m and DM. This coefficient is also proportional to a difference between two terms.
The first term, which is associated with drug-induced micelle (D ) ) (D ) - C (φ/C )(D ) becomes zero when τ ) 1 corresponding to neutral micelles. The second term is associated with micelle solvation. The relative contributions of these two terms depend on the values of τ and ν/m. If τ ) 0 and ν ) 0, eq 27 reduces to (D 21)V/φ ) K(DK DK). We therefore conclude that the sign of (D21)V The explicit expressions for the (Dij)V are cumbersome. Thus, to strongly depends on the sign of D - gain physical insight on the behavior of the diffusion coefficients, qualitative agreement with our experimental results and explana- we shall consider simplified expressions obtained by considering limit conditions. We further notice that this model describesdiffusion of nonionic drugs9 in the limit of τ ) 1 and D ) Finally, we examine (D22)V. The effect of ionic drugs can be 11)V, we consider the limit of infinite dilution described by considering the limiting expression: (D22)V 3432 Langmuir, Vol. 25, No. 6, 2009 an ethoxy group,59 and each tyloxapol consists of ∼70 ethoxy groups, we obtain ν/m ≈ 280 and ν ≈ 3400. Estimation of τ isdifficult. This quantity is expected to depend on the chemical (1 - K 1)D - (1 - K 1τ 1)τD - (1 - τ)D nature of the surfactant hydrophilic groups and charge distribution on the micelle. Thus, we examine our model by varying the value of τ from zero to one.
The surfactant nonideality term, (φ) in eq 12d, is expected 0 (K + - 2)] (28) to be close to unity at our experimental low values of φ.
Nonetheless, we have estimated it from the experimental binary In eq 28, R is directly proportional to m and a sum of two terms.
The first term is associated with drug-induced micelle charge and vanishes when τ ) 1. The second term in eq 28 is associated with micelle solvation. Interestingly, micelle solvation has (1 - φ)[1 - C (ν/m)V 22)V and (D21)V. If . 1 and DM the first term becomes K2(1 - τ)(D - Equation 29 was obtained by assuming that (L22)0ˆ ) C2 DM for indicates that the effect of ionic drugs on the surfactant main the binary tyloxapol-water system, consistent with our diffusion diffusion coefficient depends on the sign of D - model. We have also used (D2)V (1 - φ) [(L22)0/C2] 4d and 24d) and converted (L22)0ˆ into (L22)0 using eq 16c. We DK. Small values of τ imply that micelle diffusion is enhanced by drug binding. However, as τ increases, D can be calculated provided that ν/m is known.
To evaluate whether micelle solvation can be invoked to explain K. This implies that micelle diffusion is hindered in these conditions. This behavior can be physically understood our experimental diffusion results, we initially compute (Dij)V by by considering that a micelle concentration gradient at constant setting ν ) 0 and changing τ. Our experimental results and theoretical predictions are shown in Figure 3.
1 generates a concentration gradient of free drug anions and counterions. These gradients generate a net flux of drug component In Figure 3, we note that our experimental (Dij)V values with toward the micelles as discussed above. Drug cross-diffusion φ < 0.005 display some discrepancy from those at a higher φ.
can be driven either by drug ions or by counterions, depending This small deviation encountered at low surfactant concentrations can be attributed to a relatively large drug load of micelles, D/DK and the corresponding ratio in which may have a small effect on the micellization process itself.
D/∂CK)C . We obtain (∂C 1/τ from differentiation of eqs 8a,b in the limit of small φ. If τ Furthermore, we also note that the precision of diffusion ) 0, the concentration of counterions is uniform and drug diffusion measurements reduces as the solute concentration decreases.9 toward the micelles is driven by the concentration gradient of Thus, we give more relevance to our results with φ > 0.005.
drug anions. This diffusion process drives a net negative charge For (D11)V and (D12)V, our model is in good quantitative toward the micelles. The corresponding electric field drives the agreement with the experimental results if we set τ ) 0.4 ( 0.2.
negatively charged micelles in the direction opposite of that of Numerical analysis shows that the behavior of these two diffusion drug diffusion and equal to that of micelle diffusion. The net coefficients significantly depends on K. This implies that our K result is an enhancement of micelle diffusion. However, as τ value extracted from solubility measurements characterizes the increases, concentration gradients of both drug anions and behavior of (D11)V and (D12)V quite well. Similar conclusions counterions are present. Because D > the micelles becomes driven by the concentration gradient of For (D21)V, our model is in good quantitative agreement with counterions if τ is large enough. This diffusion process drives the experimental results if τ ) 0.5 ( 0.1. However, a good a net positive charge toward the micelles. The corresponding quantitative agreement for (D22)V can be obtained only if τ < 0.2.
electric field drives the negatively charged micelles in the same Although τ < 0.2 may still give acceptable predictions for (D11)V direction as that of drug diffusion. Hence, the net result and (D12)V, it predicts (D21)V values 100% larger than the corresponds to a reduction of micelle diffusion.
experimental data (see Figure 3d). Furthermore, our calculationshows that (D22)V is lower than (D2)V if τ > 0.2. On the otherhand, we experimentally obtain the opposite behavior. We have Discussion
examined whether this discrepancy can be related to inaccurate In this section, we quantitatively compare our results with the estimations of m. However, eqs 25-28 indicate that (1) m has proposed diffusion model. We set D ) a small effect on (D11)V and (D12)V; (2) (D21)V is directly 0.58 × 10-9 m2 s-1 from our drug-water diffusion data, proportional to m; and (3) a change in m has no effect on the 0.0694 × 10-9 m2 s-1 from our tyloxapol-water sign of R. Numerical examination on the (Dij)V general expressions diffusion data previously reported.9 We then set K ) 25 according confirms our conclusions. Thus, a change in m does not account to our solubility results. The tyloxapol micelle aggregation number for the observed discrepancy between (D21)V and (D22)V.
is set to m ) 12. This value was estimated from the micelle We now examine the role of micelle solvation. Equations 27 hydrodynamic volume and micelle hydration.9 It corresponds to and 28 show that micelle solvation has an opposite effect on the ∼90 octyl-phenol-ethoxylate monomers inside one micelle and behavior of (D21)V and (D22)V. As ν increases, (D22)V/(D2)V is comparable with the aggregation number of ∼100 for the increases, while (D21)V/φ decreases. Thus, ν can be used to improve octyl-phenol-ethoxylate surfactant.58 According to our diffusion the agreement between the model and the experimental results.
model, m is expected to have a significant effect only on the By varying both τ and ν, we find that the best agreement is behavior of (D21)V and (D22)V. The number of water molecules obtained for all four diffusion coefficients when τ ) 0.27 and bound to a micelle can be estimated from the chemical properties ν ) 5000. The results are shown in Figure 4. Our results with of the hydrophilic ethoxy groups of the surfactant. Because it is τ ) 0.27 and ν ) 3400 estimated from the hydration of ethoxy known that there are about four water molecules associated with groups are also included in the same figure. We can see that the (58) Tummino, P. J.; Gafni, A. Biophys. J. 1993, 64, 1580–1587.
(59) Nilsson, P. G.; Lindman, B. J. Phys. Chem. 1983, 87, 4756–4761.
Diffusion of an Ionic Drug in Micellar Aqueous Solutions Langmuir, Vol. 25, No. 6, 2009 3433 Figure 3. Ternary diffusion ratios for the naproxen(1)-tyloxapol(2)-water system ((D11)V/(D1)V, A; (D22)V/(D2)V, B; (D12)V/[C1(D1)V], C; (D21)V/
[C2DM], D). The dashed curves represent the model predictions for K ) 25 and ν ) 0. The numbers associated with each curve identify the
corresponding values of τ.
Figure 4. Ternary diffusion ratios for the naproxen(1)-tyloxapol(2)-water system ((D11)V/(D1)V, A; (D22)V/(D2)V, B; (D12)V/[C1(D1)V], C; (D21)V/
[C2DM], D). The curves represent the model predictions for K ) 25 and τ ) 0.27. The solid curves, long dashed curves, and short dashed curves
were obtained setting ν ) 5000, ν ) 3400, and ν ) 0, respectively.
experimental behavior of both (D21)V and (D22)V is reproduced of our assumption, we calculate the average number of bound fairly well also for ν ) 3400. It is expected that neglecting drug, 〈i〉, within the experimental range of micelle volume fraction electrostatic nonideality effects in the model may account for the using eq 8a. As φ increases from 0.0018 to 0.018, 〈i〉 decreases from 6.9 to 5.0. Using m ) 12 and component molar masses, We note that our proposed diffusion model assumes that drug we estimate that the drug contribution to the micelle mass binding has no effect on DM. However, drug binding may affect (ignoring the contribution of solvation) is 2-3%. For globular DM by changing the size of micelles. To examine the accuracy particles such as micelles, the estimated increase in mass is 3434 Langmuir, Vol. 25, No. 6, 2009 expected to reduce the corresponding value of DM by less than Conclusions
1%. We therefore conclude that the assumption of DM constant To quantitatively understand the experimental data of the four interdiffusion coefficients, we have built a diffusion model based Finally, we discuss the obtained value of τ. Using eqs 8a,b, on drug-micelle binding, counterion effects, and micelle we can use τ ) 0.27 to calculate the degree of counterion binding, solvation for a drug-micelle-water ternary system. We remark 〈j〉/〈i〉. Within the experimental range of micelle volume fraction, that diffusion-based transport of ionic drugs is relatively fast due 〈j〉/〈i〉 varies from 0.28 to 0.35. For ionic surfactants, it has been to the presence of counterions. Because (D11)V decreases as the experimentally and theoretically found that the degree of surfactant concentration increases, micellar systems can be used counterion binding for the corresponding micelles is significantly to bind drug molecules, thereby reducing their diffusion in a higher and ranges from 0.5 to 0.8.20,60 However, in the case of controllable fashion. Moreover, because (D12)V is negative, a ionic-nonionic mixed micelles, it has been shown that 〈j〉/〈i〉 concentration gradient of micelles may be used as a tool to further steadily decreases approaching zero as the contribution of neutral reduce drug diffusion rate from high to low micelle concentration.
surfactant to the micelle increases.61-63 Our drug-loaded tyloxapol This work provides guidance for the development of models for system is better described as a mixed micelle. Furthermore, controlled drug release in the presence of nanocarriers based on because there are about 90 neutral head groups in a tyloxapol multicomponent diffusion coefficients.
micelle, the ratio of naproxenate anions to tyloxapol head groupsis quite small within our experimental range. Thus, the obtained Acknowledgment. We are in debt with Prof. John G. Albright
small value of τ is qualitatively consistent with previous for his assistance with the Gosting diffusiometer. This work was experimental and theoretical studies on mixed micelles.
partially supported by TCU Research and Creative Activity Funds.
Supporting Information Available: Interferometric diffusion
(60) Srinivasan, V.; Blankschtein, D. Langmuir 2003, 19, 9932–9945.
(61) Hall, D. G.; Price, T. J. J. Chem. Soc., Faraday Trans. 1984, 80, 1193–
data; convective flow induced by drug diffusion. This material is available free of charge via the Internet at http://pubs.acs.org.
(62) Akisada, H. J. Colloid Interface Sci. 2001, 240, 323–334.
(63) Goldsipe, A.; Blankschtein, D. Langmuir 2005, 21, 9850–9865.

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