10884
J. Phys. Chem. B 2001, 105, 10884-10892
Electrochemistry at Lipid Monolayer-Modified Liquid-Liquid Interfaces as an Improvement to Drug Partitioning Studies Annika Ma1 lkia1 , Peter Liljeroth, Anna-Kaisa Kontturi, and Kyo1 sti Kontturi* Laboratory of Physical Chemistry and Electrochemistry, Helsinki UniVersity of Technology, P.O. Box 6100, FIN-02015 HUT, Finland ReceiVed: May 14, 2001; In Final Form: August 14, 2001
The drug partitioning between membrane and solution has traditionally been approached with bulk thermodynamic models, such as the octanol-water partitioning system. This neglects the orientational and compositional order in biological membranes. In the present study, electrochemistry at a Langmuir-Blodgett phospholipid monolayer-modified liquid-liquid interface has been employed to study the specific interactions between ionized drugs and phosphatidylcholine layers. To this end, AC voltammetric experiments and theoretical modeling accounting for the adsorption of the electroactive species have been carried out. The results point to a mechanism of charge transfer involving an adsorption step. This highlights the fact that in predicting biological activity of drugs, dynamic aspects and chemical interactions need to be considered.
1. Introduction The adsorption and uptake of drugs into their target cells is essentially dependent on their membrane activity. Thus, it is of great importance in drug development if the solute-membrane interactions of the potential drug candidates can be reliably predicted, either through preformulational partitioning experiments or theoretical quantitative structure-activity relationships (QSAR).1 The partitioning between membrane and solution has traditionally been approached with bulk thermodynamic models, such as the octanol-water partitioning system.2 Lipid bilayer membranes are, however, interphacial systems, containing order gradients inside the membrane.3-5 As a consequence, although the bulk systems in many cases produce partition coefficients comparable to those produced by biological partitioning experiments, the bulk partitioning is generally enthalpy driven whereas biological partitioning is more often entropy driven.6-9 Under physiological conditions, a considerable number of the drug molecules are ionized. Although this has long been realized, it was originally believed that charged molecules do not generally partition into a lipid environment.10 Studies of partition coefficients of octanol-water and liposome-water systems have, however, shown that whereas there may be a correlation between the octanol-water and the liposome-water partitioning coefficients for the neutral species, the octanol-water system significantly underestimates the partitioning of some ionic drugs.11,12 To improve both the nature of the partitioning phase and the predictability of ion partitioning, membrane systems such as liposomes,11,12 immobilized artificial membranes (in chromatography),13 and Caco-2 cell cultures14 have been introduced as model membranes for partitioning experiments, resulting in better correlations with biological partitioning. Another approach for obtaining information on ion partitioning is electrochemistry at an interface between two immiscible electrolyte solutions (ITIES). Reymond et al. have shown that electrochemistry at the ITIES presents a powerful tool in * Corresponding author. Tel: +358 9 451 2575. Fax: +358 9 451 2580. E-mail:
[email protected].
obtaining information on the pH dependence and potential dependence of the partitioning of ions, with the additional ability to distinguish between different charged species of a certain compound.15 However, reliable estimates on the partition coefficients of drugs in membranes might not be sufficient for accurate drug design. To develop drugs with greater efficiency and reduced side effects, it is essential that the drugs are delivered specifically to their target sites.16 The partition coefficient is a static, average parameter that only describes the affinity of a drug molecule to reside in a lipidic phase compared to an aqueous one, without specifying its preferential location or orientation in the membrane. Therefore, if partition coefficients are solely employed in estimating the membrane behavior of drugs, the concentration in other parts of the membrane can be significantly higher than at the active site of the drug. In addition, the partition coefficient does not provide information on the various drug-membrane interactions that may affect its biological activity.17 This paper describes an investigation of the validity of using partition coefficients as descriptors of membrane activity. To this end, electrochemical measurements at a biomimetic liquidliquid interface were carried out. This involves modifying an immobilized water-nitrophenyloctyl ether (NPOE) interface with a Langmuir-Blodgett monolayer of distearoyl phosphatidylcholine (DSPC) deposited at different surface pressures. Cationic drugs (propranolol, metoprolol and tacrine) and the well-characterized tetraethylammonium cation (TEA+) were used as probe ions in cyclic and AC voltammetric measurements. This yielded information both on the partitioning behavior and, with the help of a model accounting for the adsorption of the electroactive species, the detailed transfer mechanism. 2. Experimental Section Chemicals. The organic solvent in all electrochemical measurements was 2-nitrophenyl octyl ether (o-NPOE, Fluka, Selectophore). The interface was immobilized by gelling the organic phase with poly(vinyl chloride) (PVC, Sigma, very high
10.1021/jp011835e CCC: $20.00 © 2001 American Chemical Society Published on Web 10/16/2001
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J. Phys. Chem. B, Vol. 105, No. 44, 2001 10885
Figure 1. Schematic drawing of the electrochemical cell and the dipping procedure.
molecular weight). The gel was prepared by mixing 5 wt-% PVC and o-NPOE containing the organic base electrolyte and heating the mixture to 110 °C. The hot gel was then cast into the cell and left to solidify overnight. All aqueous solutions were prepared using fresh Milli-Q treated water. The lipid stock solutions were prepared in chloroform (Sigma-Aldrich, HPLC grade). The supporting electrolyte in the aqueous phase was sodium chloride (NaCl, Merck, p.a.). The organic base electrolyte tetraphenylarsonium tetrakis-4-chlorophenylborate (TPAsTPBCl) was prepared by precipitation of tetraphenylarsonium chloride (TPAsCl, Sigma, p.a.) and potassium tetrakis-4chlorophenylborate (KTPBCl, Aldrich, p.a.) as described elsewhere.18 The chemicals for studying cation transfer at the liquid-liquid interface were tetraethylammonium chloride (TEACl, Sigma, p.a.), the β-blocker drugs propranolol hydrochloride (propranolol, Sigma, reagent grade) and metoprolol tartrate (metoprolol, Sigma, reagent grade), as well as 9-amino1,2,3,4,-tetrahydroacridine hydrochloride (tacrine, Sigma, reagent grade), which is used in the treatment of Alzheimer’s disease. To measure the diffusion coefficients of the trace ions in the organic phase, they were precipitated into tetrakis-4chlorophenylborate salts in a manner similar to that used for the organic base electrolyte.18 The lipid used was 1,2-dioctadecanoyl-sn-glycero-3-phosphocholine (L-R-distearoyl phosphatidylcholine, DSPC, Sigma, >99%). All chemicals were used as received. Electrochemical Measurements. The electrochemical cell used is presented in Figure 1. The body of the cell was constructed of poly(tetrafluoroethylene) (PTFE). The interfacial area of the gel was 0.28 cm2. The following electrochemical cell was used:
Ag|AgCl|5 mM TPAsCl|10 mM TPAsTPBCl||10 mM NaCl|AgCl|Ag 5 wt-% PVC X, pH ≈ 5.8 where X denotes TEA+, propranolol, metoprolol or tacrine, typically in concentration of 50 µM. The electrochemical measurements were carried out with a computer-controlled Autolab PGSTAT100 (Eco Chemie, The Netherlands). Cyclic voltammetry was measured at sweep rates of 10, 25, 50, 75, and 100 mV/s. The AC voltammetry measurements were conducted at frequencies of 5, 10, 20, and 30 Hz using a sweep rate of 1 mV/s and an amplitude of 5 mV (rms). Each measurement was started by conditioning the system at the initial potential until the current decayed to zero. The Langmuir-Blodgett Measurements. A computercontrolled Langmuir trough (KSV Instruments Ltd., Helsinki)
was made of hydrophobic PTFE and equipped with two movable barriers of hydrophilic Delrin. The dimensions of the trough between the barriers at the starting position were 75 mm (width) and 240 mm (length). The trough was thermostated with a Lauda thermostat (C6 CS, Lauda-Ko¨nigshofen, Germany) to a temperature of 20 °C. The surface pressure was measured with a Wilhelmy plate of sandblasted platinum. The trough was placed in an earthed Faraday cage and computerized with an IBMcompatible (Intel 486 processor) personal computer via an interface unit (KSV Instruments Ltd., Helsinki) connected to the serial port. KSV Instruments Ltd. also provided the computer software. The preparation of the lipid monolayer and the deposition procedure have been thoroughly described in a previous paper.19 The substrate was now better designed for Langmuir-Blodgett deposition and was lowered through the monolayer perpendicularly (see Figure 1). The surface pressures studied in this work were 40, 50, and 60 mN/m. It is worth noting that most Langmuir monolayers are kinetically stabilized: their equilibrium spreading pressures are far lower than the typical surface pressures employed in the measurements.20 Probably the same applies for the monolayers deposited at a liquid-liquid interface. However, no changes in the properties of the monolayers were observed over a course of several hours. 3. Theory Adsorption of the electroactive species in connection with AC impedance/voltammetry has been thoroughly discussed in the literature. Delahay et al. were the first to recognize the inherent coupling between the faradaic and capacitive currents.21 Sluyters-Rehbach et al. quickly followed with a series of papers dealing in particular with reactant adsorption.22 A general treatment of admittance without assuming a specific isotherm or potential dependence of the rate constants has been put forth by Birke.23 The problem of specific ion adsorption at ITIES has been treated by Samec in a manner similar to Birke.24 We derive a model for adsorption of the electroactive species at a liquid-liquid interface with Butler-Volmer kinetics but without assuming any particular form of the adsorption isotherm. The general scheme of charge transfer is shown in Figure 2. The adsorbed ions are thought not to participate in the charge transfer reaction.24 A more general case, where both the adsorbed and free species can transfer, is analogous to a combination of surface and heterogeneous reactions at a solid electrode. It can then be shown that the global reaction is equivalent to a heterogeneous process (transfer between the free
10886 J. Phys. Chem. B, Vol. 105, No. 44, 2001
Ma¨lkia¨ et al. and where coupling between the surface concentrations and the solution concentrations in the opposing phases has been ignored. Heterogeneous kinetics are taken into account by introducing an equation that relates the faradaic current and the potential. In this case, we take a phenomenological approach and use the Butler-Volmer equation. For a recent discussion on the theories of ion transfer at ITIES, see, e.g., reference 26. The ButlerVolmer formalism at ITIES for a monovalent cation gives
if ) FA(kfcw - kbco)
(6)
kf ) k0 exp((1 - R)F/(RT)(∆wo φ - ∆wo φ0′))
(7a)
kb ) k0 exp(-RF/(RT)(∆wo φ - ∆wo φ0′))
(7b)
where Figure 2. General scheme of charge transfer with adsorption of both reactants and products.
species) with an apparent rate constant that contains contribution from the kinetics of the surface reaction.25 A material balance over the whole system, indicated by the dotted line (‚‚‚) in Figure 2, is
Jw - Jo )
∂(Γw + Γo) ∂t
(1)
where Jw is the flux from the aqueous phase to the interfacial region, Jo is the flux away from the interface, and Γw and Γo are the surface concentrations on the aqueous and the organic sides of the interface, respectively. In the presence of supporting electrolyte, the material balance (eq 1) can be written as
∂Γw ∂Γo ∂cw ∂co ) -Do |x)0 + -Dw |x)0 ∂x ∂t ∂x ∂t
(2)
The faradaic current, if, for a monovalent cation can be evaluated by considering the balance over the volume indicated by the solid line (-)
∂cw ∂Γw ∂Γw if ) Jw ) -Dw |x)0 FA ∂t ∂x ∂t
(3)
where F is the Faraday constant and A is the interfacial area. Using standard Laplace transform techniques in order to obtain the concentration gradients, the boundary conditions (eqs 2 and 3) can be Laplace transformed to yield
-(sDw)1/2∆cw - s∆Γw ) (sDo)1/2∆co + s∆Γo
(4a)
if ) -(sDw)1/2∆cw - s∆Γw FA
(4b)
where s is the Laplace variable, the ∆ notation ∆f ) hf - f dc/s, dc and cdc w and co are the concentrations at the interface set by the dc potential sweep. The surface concentrations can be expanded in Taylor series around the dc values and Laplace transformed to give
∂Γw ∂Γw ∆Γw ) ∆cw + w η j ∂cw ∂∆ φ
(5a)
∂Γo ∂Γo η j ∆c + ∂co o ∂∆wφ
(5b)
o
∆Γo )
o
where
∆wo φ
) φw - φo is the Galvani potential of the aqueous
phase with respect to the organic phase, η j ) ∆wo φ - ∆wo φdc/s
where k0 is the apparent standard rate constant (double layer effects have not been considered), R the transfer coefficient, and ∆wo φ0′ the formal potential of transfer of the electroactive ion. If the system is dc reversible, the dc surface concentrations can be obtained from the Nernst equation, and the ButlerVolmer equation can then be linearized and Laplace transformed to yield
η j)
(
)
RT if ∆co ∆cw + - dc F i0 cdc cw o
(8)
1-R(cdc)R. The capacitive current in the where i0 ) FAk0(cdc o ) w Laplace domain is given by
∂Q ∂Q ∂Q j ic ) s ∆cw + s ∆co + s w η ∂cw ∂co ∂∆ φ
(9)
o
where Q is the thermodynamic charge. The total current it is the sum of the faradaic if and capacitive ic contributions. In the Laplace domain this is
it ) if + ic
(10)
Finally, using eqs 4a, 4b, 5a, 5b, 8, 9, and 10, the admittance Y ) it/η j can be obtained. The resulting equation is rather cumbersome and some further approximations shall be made before giving the solution. In our case, the electroactive species is present in trace concentration. Therefore, we assume that the thermodynamic charge is determined solely by the supporting electrolyte
Q ) qw + FAΓw ) -(qo + FAΓo) ≈ qw ) - qo (11) where qw and qo are the excess charges due to the base electrolytes in aqueous and organic phases, respectively. Thus
∂Q ∂Q ) ≡0 ∂cw ∂co
(12)
and the last term in eq 9 is simply the normal double layer capacitance Cd ) ∂Q/∂∆wo φ. The admittance is given by
F 2A [(κwκo + κwµoσo - κoµwσw)s + (κw + κo RT µwσw + µoσo)s1/2 + 1]/[FA/i0(κwκos + (κw + κo)s1/2 + 1) +
Y)
κwσo + κoσw + (σw + σo)s - 1/2]+ Cds (13)
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J. Phys. Chem. B, Vol. 105, No. 44, 2001 10887
∆G0,wfo ) F∆wo φ0 tr,I
(16)
The results are shown in Table 1. The presence of PVC should not have a significant effect on the standard Gibbs energies of ion transfer.31 Gelling does, on the other hand, affect the viscosity and, thus, might change the diffusion coefficients. However, the measured value of DTEA,o is in line with the values reported in the literature.32,33 This indicates that gelling does not have an effect on the microviscosity of the solvent. This conclusion might not hold for larger ions whose mobility might be lowered by the polymer network in the gel. Partition Coefficients. The partition coefficients P of the univalent drug cations (I) and their corresponding neutral (N) species between water and 5% PVC-NPOE were calculated from34 Figure 3. Measured cyclic voltammograms of the probe ions normalized by the peak current. Tetraethylammonium (-), tacrine (-‚-), propranolol (- -), and metoprolol (-‚‚-). Sweep rate 50 mV/s.
where s ) iω (ω is the angular frequency, ω ) 2πf), κR ) w dc 1/2 D-1/2 R (∂ΓR/∂cR), µR ) RT/F(∂Γa/∂∆o φ), and σR ) 1/(cR DR ). If a linear adsorption isotherm is used, κR will be a constant. More complicated isotherms result in dc surface concentration dependent κR. In this work, consistent with the assumption of eq 12 (low concentrations of the electroactive species), only a linear isotherm will be considered. The dc surface concentration can be obtained from
cbw cdc ) w 1 + ξθ
(14a)
cbwθ 1 + ξθ
(14b)
cdc o )
where ξ ) (Do/Dw)1/2 and θ ) Equations 14a and 14b are only applicable for dc reversible systems and, further, slow enough dc variation of potential so that adsorption does not influence the dc surface concentrations. exp(F/(RT)(∆wo φ
∆wo φ0′)).
4. Results and Discussion
0,wfo ∆Gtr,I/N 2.3RT
(17)
The partitioning coefficients of the ionic species, log PI, were calculated using the measured Gibbs free energies of ion transfer from the water phase to the organic phase. For the neutral species, the Gibbs energies of transfer, ∆G0,wfo tr,N , are related to , through35 the ionic free energies, ∆G0,wfo tr,I
) ∆G0,wfo - ∆G0,wfo (z - dep) ∆G0,wfo tr,N tr,I tr
(18)
where ∆G0,wfo (z - dep) is the charge-dependent part of the tr transfer energy. This can be calculated using several different approaches. In this work the theoretical models of Born35 and Abraham-Liszi36 (eqs 19a and 19b) and a semiempirical method based on the one presented by Osakai et al.35 were used.
) (( )( ) ( ) )
(Born) ) ∆G0,wfo tr
(A - L) ) ∆G0,wfo tr
(
NAe2 1 1 8π0r o w
(19a)
N Ae 2 1 1 1 1 1 -1 - + -1 8π0r 1 r b o b
(19b)
Gibbs Energies of Transfer of the Probe Ions. The diffusion coefficients and standard potentials of transfer were measured with cyclic voltammetry. Typical examples of normalized voltammograms corrected for the base electrolyte current are shown in Figure 3. The diffusion coefficients were calculated from the Randles-Sˇ evcˇ´ık equation27 and the standard potentials of transfer from the following expression (for a singly charged cation):28 rev ) ∆wo φ0i + ∆wo φi,1/2
log PI/N ) -
RT γi,o RT Dw RT ln + ln + ln(1 + F γi,w 2F Do F KaR0c0(γ0)2(Dip/D0)1/2) (15)
where γi,R is the activity coefficient of ion i in phase R, Ka and Dip are the association constant and diffusion coefficient of the ion pair, respectively, and the superscript 0 refers to the organic base electrolyte. As the relative permittivity of o-NPOE is rather high (24.229), association should not be noticeable.30,31 Therefore, it was assumed that KaR0c0(γ0)2(Dip/D0)1/2 0.1 0.017 0.009
0.4 0.5 0.2
Figure 6. Plots of apparent capacitance calculated using eq 22 in the presence of ion transfer: TEA+ (-), tacrine (-‚-), propranolol (-), and metoprolol (-‚‚-). Base electrolytes (‚‚‚).
TABLE 5: Values Obtained for All Probe Molecules in the Presence of a DSPC Monolayer Deposited at Different Surface Pressures ion, Π (mN/m) TEA+,
60 TEA+, 50 TEA+, 40 tacrine+, 60 tacrine+, 50 tacrine+, 40 propranolol+, 60 propranolol+, 50 propranolol+, 40 metoprolol+, 60 metoprolol+, 50 metoprolol+, 40
Figure 5. Measured admittances for tetraethylammonium (a), propranolol (b), and metoprolol (c) transfer corrected for base electrolyte admittance (real part (-) and imaginary part (- -)) and fitted values from the theory (real part (O) and imaginary part (0)). The deposition surface pressure was 60 mN/m. The frequencies shown are 5, 10, 20, and 30 Hz. The sweep rate was 1 mV/s.
rate constant via an Arrhenius type relation
ln(k0) ) - Ea/RT + const.
(23)
Plots of this type are shown in Figure 7. If the transfer mechanism was a simple pore formation with no chemical interactions, the activation energy as a function of surface pressure could be calculated from the Uhlig formula, eq 21. In
∂Γw/∂∆wo φ (mol/cm2V) 10-9
∂Γw/∂cw (cm) 10-5
-1 × 10 × -0.8 × 10-9 2 × 10-5 ∼0 7 × 10-5 20 × 10-5 11 × 10-5 15 × 10-5 -2 × 10-9 11 × 10-5 -3 × 10-9 6 × 10-5 -2 × 10-9 17 × 10-5 -0.5 × 10-9 0.7 × 10-5
∂Γo/∂co (cm) 10-5
k0 (cm/s)
7× 0.013 4 × 10-5 0.013 4 × 10-5 0.02 1 × 10-5 >0.1 1 × 10-5 >0.1 2 × 10-5 >0.1 2 × 10-5 0.007 2 × 10-5 0.007 2 × 10-5 0.012 0.004 0.02 3 × 10-5 0.005
R 0.3 0.3 0.2
0.4 0.4 0.6 0.3 0.1 0.3
that case, it should depend on the radius of the transferring ion so that the smallest ion has the smallest slope in the ln(k) vs surface pressure plot. This is clearly not the case here: the smallest ion (TEA+) has the largest slope and, thus, the largest activation energy. This type of pore opening model has been shown to be applicable to oxygen transfer through Langmuir monolayers of stearic acid54 and to transfer of smaller ions through phospholipid monolayers at ITIES.55 With the larger, more lipophilic drug molecules, chemical interactions are important and the simple model of cavity formation is not sufficient to explain the observed behavior. Instead, a mechanism involving an adsorption step is in agreement with the experiments. Based on the experimental observations and the results obtained from the theoretical model, the specific site of adsorption of each drug in the monolayer can be assessed. The results are presented in the form of a cartoon in Figure 8. Despite its lipophilic structure, tacrine is strongly adsorbed on the aqueous side of the monolayer. This is explained by the hydrophilic amino group, which preferentially resides in the aqueous region of the monolayer. The rigid nature of the molecule and the location of the charge close to the lipophilic
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J. Phys. Chem. B, Vol. 105, No. 44, 2001 10891 molecule, only the benzene ring is able to enter the hydrocarbon domain of the monolayer. 5. Conclusions
Figure 7. Plots of logarithm of rate constant vs surface pressure yielding the activation energy as the slope. Tetraethylammonium (O), propranolol (0), and metoprolol (4).
Electrochemistry of liquid-liquid interfaces has been used to study both the thermodynamic and kinetic aspects of ionized drug transfer across phospholipid monolayers. The lipid monolayer was formed by using the Langmuir-Blodgett technique wherein a part of the electrochemical cell is used as the substrate and the monolayer at the desired surface pressure is transferred onto the liquid-liquid interface. As the majority of drugs are ionized at physiological pH, the partition coefficient of the neutral species, log PN, is not appropriate in describing their partitioning into lipid bilayers, but rather, the ionic partition coefficient, log PI, should be used. This quantity can easily be obtained by standard electrochemical methodology at liquid-liquid interfaces. The results presented in this paper demonstrate the clear difference between the partition coefficients of the ionic and neutral species. AC voltammetry experiments, along with a model incorporating the effect of faradaic adsorption, were used to elucidate the transfer mechanism and membrane activity of the drug molecules. Tacrine and metoprolol were found to be more strongly membrane active than propranolol. This is not consistent with their partitioning behavior and shows that dynamic aspects and chemical interactions need to be considered in drug design. The results were further rationalized in terms of preferred location of drugs inside the monolayer, which is of relevance for its biological activity, e.g., in the case of receptor binding drugs. Future work will concentrate on using impedance spectroscopy in order to obtain more accurate information on the potential dependence of the kinetics and adsorption involved in transferring drug molecules through the lipid monolayer. In addition, the effect of the composition of the lipid monolayer will be investigated. Acknowledgment. Financial support by the Academy of Finland and the National Technology Agency in Finland is gratefully acknowledged. The Laboratory of Physical Chemistry is part of the European Union Training and Mobility of Researchers (TMR) network “Organisation, Dynamics and Reactivity at Electrified Liquid-Liquid Interfaces (ODRELLI)”. References and Notes
Figure 8. Cartoon showing the proposed orientation of the studied drugs in the phosphatidylcholine monolayer. HG denotes the headgroup region.
part of the molecule prevent tacrine from partitioning into the hydrocarbon domain of the monolayer. The proposed location of tacrine is in accordance with partitioning experiments, where the tacrine cation has been found to be unable to penetrate into phosphatidylcholine monolayers.56 The charged group of propranolol is also adsorbed preferentially on the aqueous side of the monolayer. It is, however, likely that the naphthalene moiety will reside inside the monolayer50 due to the amphiphilic nature of propranolol. The observation of adsorption at a bare interface supports this conclusion. The interaction of metoprolol with lipids has been noted to be of more complicated nature, and the location of it in the membrane has not been established.50,57 We propose that the charged group behaves similarly to the one of propranolol, but due to the hydrophilic ether bond on the other end of the
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