J. Phys. Chem. 1994,98, 43684374
4368
Apparent Molar Volume and Apparent Molar Adiabatic Compressibility Studies of Anesthetic Molecules in Aqueous Micelle Solutions of CTAB and CTAC as a Function of Surfactant Concentration and Temperature Luchun Wang and Ronald E. VerraU' Department of Chemistry, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 0 WO Received: November 29. 1993'
Apparent molar volume and adiabatic compressibility properties of halothane and isoflurane in aqueous micelle solutions of hexadecyltrimethylammonium bromide (CTAB) and chloride (CTAC) have been studied as a function of surfactant concentration and temperature. Specific conductance measurements of the micellar systems in the presence and absence of the additive molecules were used to estimate the effect of the solubilized additives on the apparent degree of micelle dissociation. As well, 'H 7'1 relaxation and chemical shift studies of the micellized surfactant in the absence and presence of the additive were measured in an attempt to obtain complementary data regarding the solubilization sites of the additives in the micellar systems. The results show that the degree of micelle ionization, the extent of hydration of the counterions and of the head groups of the micellar systems, and the polarity of the anesthetic molecules play a role in the solubilization process. The inhalation anesthetics appear to be adsorbed in the head group region of the micelles, replacing water in this region in the case of the more hydrated micelles. Also, they penetrate to sites nearer to the a-and &methylene groups of the surfactant hydrocarbon chains when head group sites become saturated or the additive is less polar.
introduction While the practical administration of anestheticsoccurs many times a day throughout the world, the pharmacologic mechanism that produces unconsciousness and analgesia still is not fully understood. As part of a systematicstudy to addressthis problem, thermodynamic studies of inhalation anesthetics dissolved in micellar systems have been carried out to gain insight into the effect of counterions,surfactant concentration, and temperature on the volumetric properties of the anesthetics in the micellized phase. Some drugs with anesthetic properties have specific molecular structures that fit receptor sites on the cellular surface. On the other hand, inhalation anesthetics do not function in this manner as they generally have widely varying molecular structures. For example, molecular nitrogen and halogenated hydrocarbons both are anesthetics, but the potency of the former is far less than the latter. Anesthetic potency has been shown to correlate directly with the solubility of anesthetics in lipids and implies that the site of action of an anesthetic is at the lipid membrane of the cell.' A currently accepted hypothesis is that the dissolved anesthetic, acting either on the lipids or on membrane proteins, changes the fluidity or the volume of the membrane. The well-known effect of pressure antagonism of anesthetics provides some support for this hypothesis. In recent publications," we have reported on the volumetric thermodynamic properties of several hydrophobic additives in aqueous micellized ionic and nonionic surfactant systems. As part of this ongoing investigation,we report the results of apparent molar volume, apparent molar adiabatic compressibility, conductance, and proton NMR studies of solutions of the inhalation anesthetics 1-bromo- l-chloro-2,2,2-trifluoroethane(halothane) and 1-chloro-2,2,2-trifluoroethyl difluoromethyl ether (isoflurane) dissolved in aqueous solutions of micellized cetyltrimethylammonium bromide (CTAB) and chloride (CTAC) as a function of temperature. The results are compared and used to interpret the effect of the bromide and chloride counterions on the
* To whom correspondence should be addressed. *Abstract published in Advance ACS Abstracts, March 15, 1994.
solubilization process of the anesthetics and their location in the micelles and the effect of these anesthetics on the counterion binding of CTAC and CTAB micelles. The object is to use these model systems to gain further insight into the behavior of anesthetic and drug molecules in lipid transport processes in membranes and macromolecules.
Experimental Section Materials. Cetyltrimethylammonium chloride (Aldrich, 25 wt 8 solution in water) was freeze-dried. The recovered crystals were recrystallized twice from an acetone-ethanol mixture (9: 1, v/v) and vacuumdried at 60 OC. The critical micelle concentration (cmc) in water at 25 OC was determined to be 1.5 X 10-3 m from specific conductance measurements. The mean aggregation number of CTAC micelles in aqueous solution at 25 OChasbeenreported7tobeca.85,115,and 130atthecmc,0.10 M, and 0.35 M, respectively. Cetyltrimethylammoniumbromide (Sigma) was recrystallized twice froman acetone-ethanolmixture (4:1, v/v) and vacuum-dried at 60 OC. The cmc in water at 25 OC was determined to be 9 X 1 V m from specific conductance measurements. Near the cmc the mean aggregation number of CTAB micelles at 25 OC has been reported* to be ca. 80. At 0.10 M, Zana et al. have reported9 a value of 140. The value at 0.35 M is probably much larger since this concentration is above that for the formation of rodlike micelles. However, there does not appear to be a reported value of the mean aggregation number for this system in the absence of added salt. Light scattering studies10 of CTAB in the presence of a low concentration of salt suggest the mean aggregation number for rodlike CTAB micelles could be as high as 300. Halothane (Ayerst, Canada) and isoflurane (Anaquest, Canada) were used without further purification. Water used in these experiments was distilled and deionized by using a Millipore Super-Q system. Aqueous stock solutions of CTAB and CTAC were prepared and used as mixed solvents. The volatile anesthetics were transferred into the mixed solvent by means of an airtight syringe. Dead space in the flasks was made as small as possible, and the flasks were maintained airtight. All solutions were prepared on a weight basis. Solutions of the anestheticsin the mixed solvent
0022-3654/94/2098-4368%04.50/0 0 1994 American Chemical Society
The Journal of Physical Chemistry, Vol. 98, No. 16, 1994 4369
Anesthetic Molecules in CTAB and CTAC Solutions were stirred for at least 48 h prior to performing measurements soas to ensure that they had equilibrated. Theultrasonicvelocity and conductance cells also had small vapor dead space and were maintained airtight. Apparatusand Procedure. Ultrasonic velocitieswere measured at a frequency of 4 MHz with a Nusonic (Model 6080, Mapco) single transducer velocimeterby using the sing-around technique. The speed of sound, u (in ms-I), was calculated from the average round-trip period of the ultrasonic wave in the fixed path length between the piezoelectric transducer and reflector. The complete operation of the instrument and the estimated error in sound velocity have been reported previously.12 Adiabatic compressibility coefficients, @ (in units of Pa-I), were derived from the relation
0.35
halothane
(1)
where d is the solution density in kg m-3. The apparent molar adiabatic compressibility (&) of liquid solutions was calculated from the relation
where m is the molality of the solution, do is the density of the mixed solvent, r$v is the apparent molar volume, and 8, and @ are the compressibilitycoefficientsof the mixed solvent and solution, respectively. The density data were obtained with a high-precision flow digital densimeter (Model 02D, Sodev Inc.). The operation and calibration of the instrument have been previously d e ~ c r i b e d . ~ J ~ The precision in the density data was found to be k2.0 ppm. The apparent molar volume (&) of liquid solutions was calculated from the relation 1000
isoflurane
isoflurane
B = l/u2d
4,=-(do-d)+mddo
TABLE 1: Apparent Molar Volumes at M i t e Dilution, &, and Limiting Slopes, b, of Halothane dIsaflprane in Aqueous Micelle Solutions of CI'AC at 15,25, and 35 OC conc of surfactant temp (mol kgl) anesthetic ("C) 4: (01113 mol-') b (cm3 kg mol-2) 0.10 haIothane 15 103.31 f 0.17 - 6 1 f 12
M d
(3)
where d is the density of the solution and M is the relative molar mass of the solute. Data for all systems are found in the supplementary material (see paragraph at the end of the text regarding supplementary material). The solution temperatures for both the velocity and density measurements were maintained to *0.001 OC by using a closed-loop temperaturecontroller (Model CT-L, Sodev Inc.). Specific conductance ( K ) measurements were carried out at 1.5 kHz with a precision component analyzer (Wayne Kerr, Model 6425). The conductivity cell had a 50-mL capacity and used platinized platinum electrodes. The cellconstant was 1.218 cm-l, and the cell temperature was maintained constant to *0.001 OC by using a system similar to the one used for density and sound velocity measurements. The apparent degree of micelle dissociation (CY) was estimated from the ratio of the slopes of the K vs concentration plot above to below the cmc.14J5 High-resolution proton NMR experiments were performed on a Bruker AM-300 at 300 MHz. All spectra were measured at 27 OC relative to water (trace in D20)as an internal standard. 1H T1relaxation and chemical shift, 6, properties of the micellized surfactants were measured in the presence and absence of halothane and isoflurane at different concentrations of CTAC and CTAB, The precision of the 6 data is estimated to be f0.005 ppm from repeated measurements. All samples were prepared in DzO as solvent. All TIexperimentswere run using the standard inversion recovery experiment commonly found in computer program libraries. The T Idata reported are for the freezepump thaw removal of 0 2 . The uncertainty in the absolute value of T1 data is at least *5%. ReSults Values of & and q5v of halothane and isoflurane in aqueous micelle solutions of CTAC and CTAB were calculated using eq
25 35 15 25 35 15 25 35 15 25 35
103.50 f 0.18 107.34 f 0.07 119.47 f 0.17 120.02 f 0.18 123.40 f 0.14 100.22 f 0.32 100.78 f 0.24 101.60 f 0.30 114.42 f 0.27 116.01 f 0.24 116.04 f 0.28
-25 f 18 6 f 11 -75 f 13 49 f 23 2 9 f 18 16f 12 19 f 21 18 f 20 106 & 19 94 f 26 130 f 29
TABLE 2 Apparent Molar Volumes at Infinite Dilution, 4:, and Limiting Slopes, b, of Halothane and Isofluraae in Aqueous Micelle S O ~ U ~of~ ClrAB O M at 25,30, and 35 OC conc of surfactant temp (mol k g l ) anesthetic ("C) 6: (cm3mol-') 6 (cm3 kg mol-2) 0.10 halothane 25 104.35 i 0.22 -79 f 11 isoflurane 0.35
halothane isoflurane
35 25 30 35 25 35 25 35
110.28 & 0.25 120.26 f 0.21 124.47 f 0.24 125.04 f 0.22 102.83 i 0.26 107.79 f 0.25 122.25 f 0.24 126.24 f 0.19
- 6 3 f 15 - 6 8 f 12 4 3 & 13 -37 f 13 -85 f 19 -17 f 11 -191 f 18 38 f 14
TABLE 3 Apparent Molar Compressibility at Infinite Dilution, 4;, and Limiting Slopes, k, of Halothane and Isoflurane ID Aqueous Micelle Solutions of CI'AC at 15, 25, and 35 O C conc of 4; x 1014 surfactant temp k (mol k g l ) anesthetic ("C) (m3mol-' Pa-') (m3 kg mol-2 Pa-') 0.10 halothane 15 7.464 f 0.228 -73 f 29 isoflurane 0.35
halothane isoflurane
25 35 15 25 35 15 25 35 15 25 35
3.817 f 0.071 5.982 f 0.103 12.10 f 0.202 12.76 f 0.179 13.43 f 0.247 7.004 f 0.129 5.997 f 0.152 6.813 i 0.324 11.53 f 0.399 11.88 f 0.348 12.64 0.352
*
360 & 57 287 & 96 4 1 f 15 -76 f 13 -51 f 18 -53 f 6 232 f 53 165 f 41 -194 f 29 -21 f 25 -6f21
2 and 3, respectively. & and & at infinite dilution (4; and &, respectively) and the limiting slopes of these thermodynamic properties of the solubilizates in aqueous micelle solutions were determined by using a weighted least-squares method to fit the experimental data to the assumed relation 41 = 4: im where i = b and i = k forwolume and compressibilitystudies,respectively. The results for different temperatures and surfactant concentrations are shown in Tables 1 4 . Examples of the apparent molar volume (4") behavior of halothane at several temperatures in different concentrations of aqueous CTAC and CTAB solutions are shown in Figure 1, A and B, respectively. Similar, typical & results for isoflurane in aqueous solutions of CTAC and CTAB are shown in Figure 2, A and B, respectively. Some apparent molar adiabatic compressibility (&) results for halothane at several temperatures in different concentrations of aqueous solutions of CTAC and CTA3 solutions are shown in Figure 3, A and B, respectively. Examples of & behavior for
+
4310 The Journal of Physical Chemistry, Vol. 98, No. 16, 1994
Wang and Verrall
TABLE 4: Apparent Molar Compressibility at Infinite Dilution, 40, md Limiting Slopes, k, of Halothane and Isoflurrne Aqueous MiceRe Solutiow of CTAB at 25 and
125
h
35 OC mnc of surfactant temp (mol kg-1) anesthetic ("C) 0.10 halothane 25
isoflurane halothane
0.35
isoflurane
124 123
& x 1014
k (m) kg mol-2 Pa-')
+ +
135 16 143 32 46+ 17 48+ 15 252+ 15 - 6 6 36 198 50 -209 h 21 310 35
(m3 mol-'
Pa-')
12' 120
350c 25'C
+
6.089 0.221 1.451 0.393 1.804 0.298 8.881 0.212 8.124 0.268 5.810 0.289 6.896 0.391 8.231 f 0.274 9.231 0.482
35 25 30 35 25 35 25 35
w
P
+
+ + + + + +
119
?j
15 ' C
118
E
+ + +
122
-
121
-
/
123
120119
-
25 ' C
118
1
.
1
.
lo8p%-k+ 107
1
lo4
102 lo3 25
101 100
1
'C
1
0
4
8
12 m x 10' (mol/kg)
16
20
Figure 1. Apparent molar volume of halothaneas a functionof its molality in aqueous surfactant solutions: (A) in 0.10 m CTAC at 15.25. and 35 OC; (B) in 0.35 m CTAB at 25 and 35 OC.
isoflurane in aqueous solutions of CTAC and CTAB are shown in Figure 4, A and B, respectively. The value of 4; for halothane and isoflurane increases in both surfactant systems with increasing temperature. Partial molar expansibility values are shown in Table 5 . With the exception of halothane in 0.10 and 0.35 m CTAC solutions and isoflurane in 0.10 m CTAB solution, 4fi values increase with increasing temperature. Figure 5 shows a typical graph of the dependence of specific conductivity ( K ) on surfactant concentration as the number of isoflurane molecules per CTAC micelle is increased. The approximate number of solubilizate molecules per micelle can be estimated using the relationships
(g)
r = CJC,,
and C ,,
= (C - cmc)/n
(4)
where C, is the solubilizate concentraton, C,, is the micelle concentration, C is the total surfactant concentration, and n is the mean aggregation number. Whenever necessary, molality concentrationunits wereconverted to molarity units using density data reported in this paper. In writing eq 4, it has been tacitly assumed that the anesthetics are completely solubilized in the micelles at the experimental conditions used and the mean aggregation number of the micelles is the same as in the absence
: 0
15 'C
6
I
10
8F 'v6
'r
4
25%
2 0
4
0
12
16
20
m x 10' (momg)
Figure 3. Apparent molar adiabatic compressibility of halothane as a function of its molality in aqueous surfactant solutions: (A) in 0.10 m CTAC at 15, 25, and 35 O C ; (B) in 0.35 m CTAB at 25 and 35 OC.
of additive. Therefore, any reported values of the ratio r areapproximate. The results show that the slope of specific conductivity vs surfactant concentrationin the postmicellar region decreases as the ratio r increases. Values of the degree of micelle counterion dissociation (a) of CTAC and CTAB micelles containing halothane or isoflurane at different solubilizate to micelle mole ratios and temperatures are shown in Table 6.a is seen to decrease slightly with an increase of the ratio, r, for both additives, but the decrease is greater in the presence of halothane
The Journal of Physical Chemistry, Vol. 98, No. 16, 1994 4371
Anesthetic Molecules in CTAB and CTAC Solutions 15
300 1
A
13 11 13
a
r
0
1
B
11
:
Y
E
: 0 r
2
Y
13 l1 9
9 7
o ! . 0
5
3
1 0
.
, 4
.
, 8
.
, 12
9
,
16
.
.I 20
m x 10' (mollkg)
Figure 4. Apparent molar adiabatic compressibility of isoflurane as a function of its molality in aqueous surfactant solutions: (A) in 0.10 m CTAC at 15, 25, and 35 OC; (B) in 0.35 m CTAB at 25 and 35 OC.
TABLE 5 Apparent Molar Expansibility at Infinite Dilution, p , of Halothane and Imfluraw in Aqueous Micelle s o i u t i o ~oi CTAC and CTAB additive
surfactant
halothane
CTAC CTAB
isofurane
CTAC CTAB
I
1
wnc of surfactant (mol kg')
(cm3 mol-' K-1)
0.10 0.35 0.10 0.35 0.10 0.35 0.10 0.35
0.22 0.07 0.59 0.50 0.19 0.08 0.29 0.40
J%
in both micelle solutions. In all cases values of a increase slightly with increasingtemperatures. Although the absolute changes in a are only slightly greater than the magnitude of the experimental errors in the measurements, they do show a consistent trend as a function of increasing solubilizate concentration and temperature. Figure 6 illustrates the results of the change in the chemical shift (Aa) of specific protons of the micellized CTAC cations induced by solubilized halothane and isoflurane. The proton signals for each surfactant show a smaller upfield shift in the presence of halothane compared to isoflurane. A typical result of the studyof the effect of solubilized anesthetic molecule on the relaxation rate, R = l / T , , of specific protons of micellized CTAB cations is shown in Figure 7. Halothane molecules are found to have more of an effect on the R values of the protons located in the head group region of the CTAB micelles whereas isoflurane (not shown) has an effect on the R values of the protons of the a-,&, and y C H 2 groups of the long alkyl chain of the surfactant but shows virtually no effect on the relaxation rate of the N-CH3 protons. The R values of the micellized surfactant protons generally increase with an increase in the anesthetic/micelle mole ratio (Figure 7).
Discussion Comparison of T b e m ~ d y ~ mProperties i~ of Anesthetic Molecules at Infinite Dilution in Micellar Systems. The ther-
.
,
,
.
2
.
3
, 4
.
, 5
.
, 6
m x 10' (mollkg)
Figure 5. Specific conductivity vs CTAC concentration at 25 O C for different mole ratios of isoflurane/micelle: (e) r = 8; (m)r = 14; (a) r = 0.
TABLE 6: Effect of Temperature and Solubllizate/MiceUe Mole Ratio on the Degree of Micelle Counterion Dissociation
(4
surfactant temp ("C) CTAC
15 25 35
CTAB
25 35
4 solubilizate/micelle mole ratio isoflurane halothane 0 0.344 0.344
8 14 0 8 14 0 8 14 0 11 19 0 11 19
0.337 0.327 0.357 0.350 0.341 0.400 0.394 0.387 0.261 0.251 0.241 0.212 0.263 0.254
g
0.330 0.321 0.357 0.347 0.338
0.400 0.390 0.381 0.261 0.241 0.235 0.212 0.260 0.250
modynamic properties #,: 4;. and of hydrophobic solubilizates dissolved in aqueous micellar solutions reflect solubilizate mixed solvent interactions and can be used to predict the approximate solubilization sites of such molecules in micellar systems. For example, in a hydrophobic environment such as an oil, water-insoluble solubilizates have relatively larger 6 values due to the loose packing of hydrocarbonchains.' By comparison, in an aqueous environment the hydrophobic solubilizates are expected to have smaller values of 4: because of the hydrophobic hydration effect, Le., the inducement of higher density states of water by the hydrophobic molecule. With respect to 4; data, relatively lower values of this property for hydrophobic solubilizates reflect their location in a more hydrophilic environment whereas larger values are expected when such molecules locate in a hydrophobic environment. Finally, positive values of are expected for hydrophobic solutes in an aqueous medium16 since there is less free space in the cosphere of a hydrophobic solute in water. Generally, electrostatic hydration effects are expected to decrease values. Partial molar volume data at infinite dilution of several anesthetic molecules dissolved in water and decane and the molar volumes of the anesthetics in their liquid state at 25 OC have been
4372 The Journal of Physical Chemistry, Vol. 98, No. 16, 1994 0.04
0.03
0.02
001
~
4
0.00
-0.01
-0.02 N-CH3 a-CH2
P-CH2
yCH2
-(CH2),,-
-CH3
Group
Figure 6. Changes in NMR chemical shifts (As) of the protons of micellized CTAC hydrocarbon chains in the presence of anesthetic: halothane (a), r = 18; isoflurane (e),r = 18. 2.0
1.5
-B F
U
1.o
0.5
1
.
I
I-CH3 a-CH2
.
I
'
B-CH2
I
yCH2
.
I
-(CH2),-
.
I
-CH3
Group
Figure 7. NMR spin-lattice relaxation rates of the protons of micellized CTAB hydrocarbon chains in the presence of halothane: (a) r = 0; (e) r = 18; (m) r = 32.
previously r e ~ o r t e d . ' ~Values J~ of 4: for halothane in the pure liquid state, water, and decane are 106.3, 102.6, and 114.5 cm3 mol-', respectively, and those for isoflurane in the pure liquid state, water, and decane are 123.7, 113.0, and 135.4 cm3 mol-', respectively. The relatively low solubility of these molecules in water would make the absolute values for 4: in this solvent prone to more error, but it is clear from consideration of these data that there is agreement with the general rule that hydrophobic molecules have a lower volume when dissolved in water as compared to a hydrocarbon environment. A comparison of the data for 4: at 25 OC shown in Tables 1 and 2 with the values from ref 18 shows that the magnitudes of the 4: properties obtained in this work for halothane and isoflurane at infinite dilution in
Wang and Verrall CTAB and CTAC micelle systems are between those expected for these anesthetic molecules dissolved in water and in the pure state. There are several features of the 4: results that provide information about the solubilization sites of the anesthetic molecules in these micellar systems. The magnitude of 4: of the anesthetic molecules at a given temperature and surfactant concentration is always larger in CTAB than in CTAC micellar systems (cf. Tables 1 and 2). This difference is also seen to increase with increasing temperature and surfactant concentration. As well, with the exception of 4: of isoflurane in CTAB, 4: of the anesthetics decreases with increasing surfactant concentration at a given temperature. Someof these results can be explained by the relative differences in the degree of hydration of the micelle counterions and in the surface charge densities of the micelles. Estimates of micelle counterion dissociation (Table 6) measured near the cmc show that B r is more tightly bound than C1- to the cationic micelles. Consequently, the micelle surface charge density of CTAB micelles is lower than CTAC micelles. As well, B r is more weakly hydrated than C1- anions. From these facts one can postulate that the cationic micelle head group region in the presence of B r counterions is relatively more closely packed and has less water, Le., is drier, than in the presence of C1- counterions. Therefore, solubilization of the anesthetic molecules in the head group region of the micelles is consistent with a larger 4: of the anesthetics in the CTAB systems. Since micelles are likely to be less hydrated at higher surfactant concentrations and a increaseswith increasing temperature, both properties would contribute to a relatively less hydrophilic micelle-water interface in the case of CTAB systems. The decrease in 4: of the anesthetic molecules with increasing surfactant concentration infers that they are in a more hydrophilic environment when the concentration of micelles is greater. This is consistent with the hypothesis that they are solubilized at or near the water-micelle interface. The polarities of the anesthetic molecules are also an important parameter to consider in a discussion of the results. Estimates of the permanent dipole moments of halothane and isoflurane were calculated to be 0.87 and 0.15 D, respectively, using the method of vector summation of group contributions.19 The small partition coefficient of isoflurane between water and the gas phaseZooffers supporting evidence of the weaker polarity of isoflurane. Halothane in particular could effectively replace water molecules at the micelle-water interface. The increase of 4: of isoflurane as a function of CTAB concentration suggests that, because of its lower polarity, it may penetrate below the micelle water interface at higher CTAB concentrations. The rather larger magnitude of of the anesthetic molecules in CTAB systems is greater than normally expected of hydrophobic solutes in water.16 It may be the case that the temperature dependence of hydrophobic hydrations is not so much an issue as is the contribution of the intrinsic expansion of the anesthetic molecules when they are located around the relatively hydrophobic CTAB head groups. The magnitude of for the anesthetic molecules dissolved in CTAC micelles is closer to values expected of hydrophobic molecules in an aqueous environment. However, they are still large and also reflect a contribution of the intrinsic expansion of the anesthetic molecules. 4: results appear to offer a refinement of the general discussion concerning solubilization sites derived from 4: results. At a given surfactant concentration and temperature, 4: of halothane showsonly slight differences between CTAB and CTAC micelles (cf. Tables 3 and 4). For 0.10 m surfactant, values are only slightly larger in CTAB than in CTAC. At 0.35 m they are approximately the same. On the other hand, of isoflurane in CTAC is significantly greater than in CTAB systems at both 0.10 and 0.35 m surfactant concentration.
e
Anesthetic Molecules in CTAB and CTAC Solutions The observed compressibility of micellar solutions generally depends on two major factors:21(i) the compressibility of the hydrocarbon core and (ii) the interaction between the head groups. Solutes added to aqueous micelle solutions may affect the compressibility by disrupting water structure around the micelle head groups and by occupying free space between surfactant chains in the micelles. The magnitude of 4: for halothane in both CTAB and CTAC micelles is slightly less positive than previously reported6 by us for the compound 2-tert-butyl-4methoxyphenol (BHA) in CTAC where it was rationalized that BHA was located at the micelle-water interfacial region. Since there are some similaritiesin the polarities of halothane and BHA, the less positive value of 4: of halothane is consistent with the polar nature of halothane and its potential to locate in the hydrated head group region of the micelles. The significantly more positive magnitude of 4: for isoflurane in CTAC solutions is similar to values obtained5 for 2,6-di-tert-butyl-4-methylphenol (BHT), a hydrophobic solute, dissolved in CTAB micellar systems. As for the case of BHT in CTAB, isoflurane appears to penetrate beneath the outer hydrated region of the head groups of CTAC micelles, locating beneath the micelle head groups. The 4: values of isoflurane in CTAB systems are similar to those reportedS for BHA in CTAB. However, it would appear that there is no need for the weakly polar molecule to seek a hydrophobic location beneath the CTAB head groups as the less solvated outer CTAB head group region can accommodate the isoflurane molecule at infinite dilution. The temperature dependence of 4: of halothane at constant CTAC concentration shows the presence of a minimum in the temperaturerange 15-35 OC (Table 3). A similar behavior could not be verified for halothane in aqueous CTAB solutions because of the high Krafft point of CTAB, Le., 25 OC. However, 4: values in both CTAB and CTAC surfactant systems increase from 25 to 35 OC for all surfactant concentrations studied. The thermal coefficient of the compressibility property of halothane in these surfactant systems over this narrow temperature range is ca. (1-2) X lo-'$ m3 mol-' Pa-' K-l and is similar to values obtainedfor the aqueous surfactant solutions.6 This may indicate that the thermal effect on the compressibility of the micelles dominates this change in the property. Comparison of the Thermodynamic Properties of Anesthetics at Finite Concentrations in Micellar Systems. The concentration dependence of the volume and compressibility properties of the anestheticmolecules dissolved in CTAB and CTAC micelles shows unusul behavior for some experimentalconditions. Breaks in the concentrationdependence of 4, and &of halothane occur in 0.10 and 0.35 m CTAC at 25 and 35 OC. The magnitude of these changes cannot be accounted for by experimentalerror. No such anomalies occur at 15 OC. The changes in 4, occur at ca. 12 X 10-3 and 16 X 10-3 m anesthetic in 0.10 and 0.35 m CTAC, respectively, and for I$k they occur at ca. 8 X l e 3 and 12 X m anestheticinO.lOand0.35 m CTAC,respectively. Nounusual behavior is observed in the concentration dependence of of halothane in CTAB. However, abrupt changes in &occur at ca. 12 X 10-3 and 10 X 10-3m halothane in 0.10 and 0.35 m CTAB, respectively, at 35 OC. There is no evidence of unusual concentration dependence of 4,. or f$k of isoflurane in CTAC systems at the experimental conditions studied. For isoflurane in CTAB systems, no breaks are observed in 4, but the & results are very similar to those found for & of halothane in CTAB; i.e., breaks in 4 k occur at precisely the same anesthetic concentrations as observed for halothane in CTAB. The changes that occur in the 4, and 4 k properties of the anestheticmolecules are consistent with those expected for species transferring to a more hydrophobic-like environment. Two possible explanations for this observation can be considered. Results at infinite dilution indicate that the anesthetics solubilize
The Journal of Physical Chemistry, Vol. 98, No. 16, 1994 4373 in the hydrated head group region, particularly in the case of CTAC micelles. At higher concentrations,once the surface sites have become saturated, the anesthetic molecules may be forced to locate at relatively more hydrophobic sites just beneath the head groups of the micelles. An alternate explanation is predicted on the possibility that the anesthetic molecules may induce a change in micelle structure. Sphere-to-rod transitions in CTAB micelles have been reported10v22in both the presence and absence of added salts for surfactant concentrationsgreater than 0.10 m. The concentrations at which these transitions occur also depend upon the property measured. There has been no report of such structural changes occurring in CTAC micelles at the relatively low surfactant concentrations studied in this work. An interesting feature of the unusual behavior in & and f$k is that the breaks occur consistently in the case of halothanedissolved in CTAC micelles, Le., when the more polar anesthetic molecule is dissolved in the more hydrated micelles. The anesthetic concentrations at which the thermodynamic properties show abrupt changes are independentof temperature but increasewith surfactantconcentration. This latter result shows that the changes depend upon the number of additive molecules per micelle since the ratio is greater at the lower surfactant concentration, i.e., lower micelle concentration. As well, the breaks in the compressibility property occur at lower anestheticconcentrationsthan do the breaks in 4,. The compressibility property (second-order derivative of G with respect to pressure) is more sensitive than volume (first-order derivative) to structural changes in the liquid phase, and this could be a reason for the observed differences. In the case of the anesthetic molecules dissolved in CTAB micelle systems, abrupt changes occur only in qjk at 35 OC in 0.10 and 0.35 m CTAB. The onset of the changes in $k of both halothane and isoflurane occurs at the same additive concentrations, 12 X 10-3 m in 0.10 m CTAB and 10 X l e 3 m in 0.35 m in CTAB. While it is expected that rod-shaped CTAB micelles exist in 0.35 m CTAB solutions in the absence of additive, there has been no reported evidence of their existence in 0.10 m CTAB. There is far less evidence for structural changes in CTAC micelles at lower surfactant concentrations. However, such an explanation cannot be completely ruled out as replacement of water molecules at the micelle-water interface by the larger halothane molecules could cause some molecular rearrangement and change in surface forces. The lack of any irregularities in and & of isoflurane in CTAC systems does suggest that this relativeiy nonpolar molecule is solubilized on the hydrophobic side of the micelle-water interface. Dynamic light scattering studies of these ternary systems are necessary to determine whether induced changes in the micelle structure by the additives are the source of the unusual behavior of 4, and & It can be concluded from the thermodynamic studies that the more polar anesthetic has a propensity to locate on the hydrophilic side of the micellewater interface at low concentrations. As its concentration increases, it changes location to the hydrophobic side of the interface. It remains unclear whether this occurs without a change of micelle structure or is consonant with such a change. Some systems show significant temperature dependence of the slopes of 4, and $k vs concentration in the dilute regions (cf. Tables 1-4). Generally,within the experimentalerror, the slopes are negative and become more positive with increasing temperature. Exceptions are the cases of halothane and isoflurane dissolved in 0.35 m CTAC where b remains approximately constant with increasingtemperature. The positive temperature dependence of the slopes is consistent with the behavior of hydrophobic solutes in water. NonthermodynamicPropertiesof the Surfactants. The results of measurements of some nonthermodynamic properties of the surfactants in the presence of the anesthetic molecules provide further support for the additives locating in the micelle-water interface. Changes in the 1H NMR chemical shifts of micellized
4314 The Journal of Physical Chemistry, Vol. 98, No. 16, 1994 hydrocarbon chains of CTAC in the presence of halothane or isoflurane (Figure 6 ) show that greater chemical shift changes occur for N-CH3 and a-CH2 proton resonances in the presence of isoflurane. As well, halothane-inducedchanges in the NMR spin-lattice relaxation rates (R) of the various protons of the CTAB surfactant chains are greatest for the N-CH3, a-CH3, and @-CH2groups (Figure 7). For the case of isoflurane dissolved in CTAC micelles, R changes the most for a-CH2 and p-CH2 protons as the additive to micelle mole ratio increases. These typical results support the conclusion that the anesthetic molecules locate at the micelle-water interface. A relatively nonpolar molecule like isoflurane appears to locate just beneath the head groups in the more hydrated CTAC micelles. The drier interfacial region of the CTAB micelles does not provide so clear a distinction between the solubilization sites of halothane and isoflurane. The results of studies of the change in degree of micelle counterion dissociation also confirm the location of the anesthetic molecules in the head group region of the micellar system. The increase in counterion binding to the micellar surface with increasing anesthetic concentration (Table 6 ) can be accounted for by a decrease in the local dielectric constant as the anesthetic molecules replacewater molecules at the micelle-water interface. This also has the effect of increasing the hydrophobicity of the interface.
Conclusions This study of the solubilization of anesthetic molecules in micelles of a common cationic species but differing counterions has shown that thedegreeof micelle ionization (a) and thedegree of hydrationof the micelle surface and counterions play important roles in determining where the anesthetic molecules solubilize in these micellar systems. The surface charge density of the micelle surface depends upon a. As well, the replacement of water of hydration at the micelle-water interface by anesthetic molecules can affect the balance of intermolecular forces at the interface and may cause changes in micelle structure. Light scattering studies are required to determine if there is a threshold anesthetic concentration for inducing change in micelle structure. It can be inferred from the results reported here that, in the case of the relatively more hydrated micelles, the more polar halothane molecule replaces water molecules at themicelle-water interface, rendering the interfacial region more hydrophobic. On the other hand, the relatively nonpolar isoflurane molecule may penetrate to sites just beneath the head groups, in the vicinity of
Wang and Verrall the a- and @-methylenegroups of the surfactant hydrocarbon chain. This process can also occur when solubilizationsites outside the head group becomesaturated. These results appear tosupport the modeP that anesthesia is an interfacial phenomenon at low concentrations, and anesthetic molecules only penetrate into a more hydrophobic environment at higher concentrations.
Acknowledgment. We are grateful to the Natural Sciences and Engineering Research Council of Canada for their financial support. Supplementary Material Available: Tables of ultrasonic velocity, density, apparent molar volume, apparent molar compressibility, and adiabaticcompressibility coefficient data for halothane and isoflurane in aqueous solutions of CTAB and CTAC at different temperatures ( 10pages). Ordering information is given on any current masthead page. References and Notes (1) Winter, P. M.; Miller, J. N. Sci. Am. 1985, 252, 124. (2) Alauddin, M.; Verrall, R. E. J. Phys. Chem. 1986, 90.,1647. (3) Alauddin, M.; Verrall, R. E. J. Phys. Chem. 1984, 88, 5725. (4) Alauddin, M.; Verrall, R. E. J. Phys. Chem. 1987, 91, 1802. (5) Alauddin, M.; Verrall, R. E. J. Phys. Chem. 1989, 93, 3724. (6) Wang, L.; Verrall, R. E. J. Colloid Interface Sci. 1993, 160, 380. (7) Malliaris, A.; Lang, J.; Zana, R. J. Colloid Interface Sci. 1986,110, 237. (8) Leibner, J. E.; Jawbus, J. J. Phys. Chem. 1977,81, 130. (9) Zana, R.; Muto, Y.; Esumi, K.; Meguro, K. J . Colloid InrerfaceSci. 1988,123, 502. (IO) Imae, T.; Kamiya, R.; Ideda, S. J. Colloid Interface Sci. 1985,108, 215. (11) Gamey, R.; Boe, R. J.; Mahoney, R.; Litovitz, T. A. J. Chem. Phys. 1969, 50, 5222. (12) Alauddin, M.; Verrall. R. E. J. Phys. Chem. 1988, 92, 1301. (13) Picker, P.; Tremblay, E.; Jolicoeur, C. J. Solution Chem. 1974, 3, 377. (14) Evans, H. C. J. Chem. SOC.1956,579. (15) Zana, R. J. Colloid Interface Sci. 1980, 78, 330. (16) Roux, G.; Perron, G.; Desnoyers, J. E. J. Solution Chem. 1978, 7, 639. (17) Mori, T.; Matubayasi, N.; Ueda, I. Anesthesiology 1982,57, A298. (18) Fukushima, K.; Kamaya, H.; Ueda, I.J. Pharm.Sci. 1990,79,893. (19) Weast, R. C. CRC Handbook of Chemistry and Physics, 5th ed.; CRC Press: Boca Raton, FL, 1973. (20) Lerman, J.; Willis, M. M.Anesthesiology 1983, 59, 554. (21) Blwr, D. M.; Gormally, J.; Wyn-Jones, E. J. Chem. Soc., Faruday Trans. 1 1984.80, 1915. (22) Backlund,S.;Hailand, H.; Kvammen, 0.J.; Ljosland,E. Acta. Chem. Scand., Ser. A 1982, A36, 698. (23) Yoshida, T.;Taga, K.; Okabayashi,H.; Matsushita,K.; Kamaya, H.; Ueda, I. J. Colloid Interface Sci. 1985, 109, 336.
