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Micellization in Binary Mixtures of Amphiphilic Drugs
JOURNAL OF COLLOID AND INTERFACE SCIENCE ARTICLE NO.
179, 478–481 (1996)
0240
Micellization in Binary Mixtures of Amphiphilic Drugs DAVID ATTWOOD,*,1 VICTOR MOSQUERA,† LAURA NOVAS,†
AND
FELIX SARMIENTO‡
*Department of Pharmacy, University of Manchester, Manchester M13 9PL, United Kingdom; and †Departamento de Fisica de la Materia Condensada and ‡Departamento de Fisica Aplicada, Facultad de Fisica, Universidad de Santiago, Santiago de Compostela, Spain Received July 19, 1995; accepted October 25, 1995
The composition of the micelles in binary mixtures of the cationic amphiphilic drugs (a) chlorpromazine and promethazine and (b) chlorpromazine and adiphenine has been determined from an analysis of the variation of the critical micelle concentration, as measured by conductivity techniques, as a function of solution composition. Evaluation of the nonideality of mixing of the components of the mixed micelles using a regular solution approximation revealed ideality of mixing in the chlorpromazine/promethazine system. Mixing in the chlorpromazine/adiphenine system did not deviate significantly from ideality despite differences in the structure and packing characteristics of these two drugs. q 1996 Academic Press, Inc.
Key Words: mixed micelles; drugs; critical micelle concentrations.
INTRODUCTION
Several studies on the nonideality of mixing in a wide variety of different surfactant mixtures (see review by Holland (1) have shown a strong influence of the nature of the charge of the two surfactants. Nonideal interactions, as quantified by the dimensionless interaction parameter b, become progressively stronger in going from mixtures of the same surfactant type to those of opposite charge. The magnitude of b has also been reported (1) to be influenced by structural differences between mixed surfactants, for example, by changes in the relative hydrocarbon chain lengths of the two surfactants or changes in the oxyethylene chain length in mixtures involving a nonionic surfactant. In the present study we have examined nonideality of mixing in binary mixtures of amphiphilic drugs. The selected drugs, which are of similar charge (cationic), are either phenothiazine derivatives having rigid, almost planar hydrophobic ring systems (chlorpromazine and promethazine) or are based on the flexible diphenylmethane hydrophobic moiety (adiphenine). The purpose of the study is to identify any differences in nonideality of mixing within micelles composed of the two phenothiazine drugs and those formed by mixtures of a phenothiazine and a diphenylmethane drug. 1
To whom correspondence should be addressed.
478
0021-9797/96 $18.00 Copyright q 1996 by Academic Press, Inc. All rights of reproduction in any form reserved.
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JCIS 4116
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6g0e$$$641
The two types of drug under consideration have different patterns of association. Adiphenine hydrochoride, in common with other diphenylmethane derivatives, associates by a micellar process (2) forming small micelles at a clearly defined critical micelle concentration (cmc). The phenothiazine drugs have been the subject of recent interest due to their unusual association characteristics. Abrupt inflections in the concentration dependence of solution properties in water and dilute aqueous electrolyte were assumed by earlier workers to be indicative of micellar association and the inflections were identified with the cmc of typical surfactants (3, 4). However, recent NMR studies (5) of the change in chemical shift of aromatic protons and C atoms over a wide concentration range in solutions of chlorpromazine in D2O provide evidence for a limited association below this inflection point. Similar conclusions have been drawn from direct measurements (6) of the monomer concentration in aqueous solutions of promethazine using membrane electrodes selective for the cation of this drug and from heat conduction calorimetry (7), osmotic (8) and density (9) studies for aqueous solutions of several phenothiazines. Furthermore, static light scattering and ultrasound velocity measurements have identified additional discontinuities of solution properties at higher solution concentrations. (10, 11). The micellar properties are independent of concentration over the concentration range between the first and second critical concentrations, and NMR studies (5) have suggested offset concaveto-convex vertical stacking of the phenothiazine molecules within the micelles, with alkyl side chains on alternate sides of the stack. Hence, although the self-association of the phenothiazine drugs is by a stacking process similar to that envisaged for the tricyclic dyes (12), the association is not a continuous process as in the dye solutions but is characterised by a series of critical concentrations at which discernible changes in solution properties occur. The first (but not subsequent) of the critical concentrations, which represents the concentration at which stable micellar units are formed, behaves in a similar way to the cmc of typical surfactants when electrolyte is added to the solution; i.e., it decreases in accordance with the predictions of the mass action theory of micellization (11). Similarly,
04-25-96 15:37:56
coida
AP: Colloid
MICELLES IN BINARY MIXTURES OF AMPHIPHILIC DRUGS
FIG. 1. Conductivity, k, as a function of molality, m, for mixtures of chlorpromazine and adiphenine with mole fractions of chlorpromazine of s, 0.00; h, 0.20; n, 0.40; L, 0.50; q, 0.60; l, 0.80; and j, 1.00.
the use of the first critical concentration in calculations of the thermodynamic parameters for micellization gives values which are in agreement with experimentally determined values (13). In this study, the variation of this critical concentration (subsequently referred to as the cmc) with changes in the composition of a binary mixture of the phenothiazine drugs, either together or in combination with adiphenine, has been used to determine the composition of the mixed micelles and the nonideality of mixing within them. EXPERIMENTAL SECTION
Materials. The hydrochlorides of chlorpromazine [2chloro-10-(3-(dimethylamino)propyl)phenothiazine], promethazine [ 10 - ( 2 - ( dimethylamino ) propyl ) phenothiazine ] and adiphenine [2-diethylaminoethyl diphenylacetate] (Sigma Chemical Co.) conformed to the purity requirements of the British Pharmacopoeia and as such contained not less than 98.5% of the specified compound. Conductivity measurements. The conductivity of the binary mixtures was measured at 30 { 0.017C using a specific conductivity meter (Kyoto Electronics, Type C-117). The cell constant was determined with aqueous solutions of KCl over the appropriate concentration range using the molar conductivity data of Shedlovsky (14) and Chambers et al. (15). Water (twice distilled and degassed) was progressively added to concentrated aqueous solutions of chlorpromazine/promethazine and chlorpromazine/adiphenine mixtures of known molality and composition using a peristaltic pump (Dosimat, Model-655, Metrohmn AG) under the control of a Hewlett–Packard Vectra computer. RESULTS AND DISCUSSION
Figure 1 shows conductivity data for mixed systems of chlorpromazine and adiphenine for a range of compositions; similar
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6g0e$$$641
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479
FIG. 2. Variation of cmc with composition of the chlorpromazine/promethazine system. Top curve represents the total concentration of free monomeric surfactant against mole fraction of chlorpromazine in mixed micelle, x m2 , as calculated from Eq. [5]. Bottom curve represents the variation of cmc with mole fraction of chlorpromazine in the system, x2 .
plots were obtained for mixtures of chlorpromazine and promethazine. The curvature of these plots in the region of the cmc is not only a consequence of a low aggregation number of the drug micelles but also reflects changes in the composition of the mixed micelles on dilution at concentrations close to the cmc (16). Since there are no clear inflection points in these plots, cmc values were determined from the plots of molal conductivity as a function of (molality)1/2 as recommended by Mysels and Mukerjee (17). The variation of the cmc as a function of the mole fraction of chlorpromazine in both mixed systems is shown in Figs. 2 and 3.
FIG. 3. Variation of cmc with composition of the chlorpromazine/adiphenine system. Top curve represents the total concentration of free monomeric surfactant against mole fraction of chlorpromazine in mixed micelle, x m2 , as calculated from Eq. [5]. Bottom curve represents the variation of cmc with mole fraction of chlorpromazine in the system, x2 .
coida
AP: Colloid
480
ATTWOOD ET AL.
Changes in the distribution of the components of each system between monomeric and micellar phases as a function of the total solution composition were evaluated by analysis of the variation of the cmc with composition using a method proposed by Motomura and co-workers (18) which is based on excess thermodynamic quantities. In this treatment the composition of the mixed micelle formed by surfactants 1 and 2, is derived using the relationship
cmc has enhanced mole fraction in the mixed micelle, as might be expected. An estimation of the nonideality of mixing in the mixed micelles of the two systems was obtained using the simplified approach proposed by Holland and Rubingh (19). In this model the nonideality of mixing of components is quantified using a dimensionless interaction parameter b which may be interpreted as an excess free energy of mixing parameter. According to this model
xV 2m Å xV 2 0 (xV 1 xV 2 /cmc) (Ì cmc/ ÌxV 2 )T,p / [1 0 d dc £1,c £2,d /( £1,c £2 xV 1 / £2,d £1 xV 2 )],
[1]
where cmc Å ( £1 x1 / £2 x2 )cmc
[2]
xV i Å £i xi /( £l xl / £2 x2 ) m i
m i
m 1
(i Å 1, 2) m 2
xV Å £i x /( £1 x / £2 x )
(i Å 1, 2)
[3] [4]
and x1 and x2 are the mole fractions of surfactants 1 and 2 in the binary system; x 1m and x 2m are the mole fractions of surfactants 1 and 2 in the mixed micelle; £1 Å £1,a / £1,c and £2 Å £2,b / £2,d ; £1,a and £1,c are the number of cations and anions produced on dissociation of surfactant 1 and £2,b and £2,d are the number produced on dissociation of surfactant 2. The drugs under investigation are 1:1 electrolytes with identical counterions, i.e., £1,a Å £1,c Å £2,b Å £2,c Å 1 and hence cmc Å 2cmc.
The Kronecker delta, d dc , for systems in which counterions are identical is 1 and hence Eq. [1] reduces to xV 2m Å xV 2 0 2(xV 1 xV 2 /cmc) ( Ìcmc/ ÌxV 2 )T,p .
[5]
The bottom curves of Figs. 2 and 3, showing the variation of the experimentally measured cmc with the composition of the system, were fitted to an equation of the form cmc Å a(xV 2 ) 2 / b(xV 2 ) / c,
[6]
where a, b, and c are constants, thus allowing the precise determination of ( Ìcmc/ Ìx2 )T,p and hence the evaluation of xV 2m as a function of cmc from Eq. [5]. The top lines of Figs. 2 and 3 show the variation of the cmc with the composition of the mixed micelles as determined by this method. Figures 2 and 3 express the relationship between the composition of the micelle and that of the solution in equilibrium with it. The computed (top) curves give the equilibrium total monomeric concentration for a given micellar composition, while the lower curve gives the mole fraction of each component in monomeric form corresponding to this equilibrium. Inspection of these figures shows that the drug with the lower
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bÅ
ln[x2cmc/((1 0 xV 1m ) C *2 )] (xV 1m ) 2
[7]
where C *2 is the cmc of the pure surfactant 2. Values of b of 00.01 and 00.15 were calculated for chlorpromazine/ promethazine and chlorpromazine/adiphenine systems, respectively. Any deviations from ideality ( b Å 0) for these mixtures arise from structural differences of the hydrophobic groups since all three drugs are cationic and fully ionized at the pH of the measurements. In view of the structural similarities between chlorpromazine and promethazine it is not unexpected that their mixing should be an ideal process. In contrast to these phenothiazine drugs, which have rigid, almost planar, hydrophobic systems, adiphenine exhibits flexibility around the central carbon atom of the diphenylmethane moiety. As a consequence, there are differences in the packing modes of these two types of drug within their aggregates. Evidence from recent NMR measurements (5) suggests a convex-to-concave vertical stacking of phenothiazine molecules which is not favored by the more flexible hydrophobes of diphenylmethane derivatives such as adiphenine. The b values calculated for chlorpromazine/adiphenine mixtures, although more negative than those for the mixtures of the phenothiazine drugs, are of similar order of magnitude to those for mixtures of cationic surfactants (for example, mixtures of hexadecyltrimethylammonium chloride and dodecylpyridinium chloride in 0.15 M NaCl have a b value of 00.2 at 307C) (20) suggesting that the structural differences between the two drugs do not lead to any appreciable nonideality of mixing. ACKNOWLEDGMENT The authors thank the Xunta de Galicia for financial support.
REFERENCES 1. Holland, P. M., in ‘‘Mixed Surfactant Systems’’ (P. M. Holland and D. N. Rubingh, Eds.), Chapter 2. ACS Symposium Series 501. Am. Chem. Soc., Washington DC. 1992. 2. Attwood, D., J. Pharm. Pharmacol. 28, 407 (1976). 3. Attwood, D., and Florence, A. T., ‘‘Surfactant Systems,’’ Chapter 4. Chapman & Hall, London, 1983. 4. Attwood, D., Adv. Colloid Interface Sci. 55, 271 (1995).
coida
AP: Colloid
MICELLES IN BINARY MIXTURES OF AMPHIPHILIC DRUGS 5. Attwood, D., Waigh, R. D., Blundell, R., Bloor, D., The´vand, A., Boitard, E., Dube`s, J. P., and Tachoire, H., Mag. Res. Chem. 32, 468 (1994). 6. Wan Bahdi, W., Mwakibete, H., Bloor, D. M., Palepu, R., and WynJones, E., J. Phys. Chem. 96, 918 (1992). 7. Attwood, D., Boitard, E., Dube`s, J. P., and Tachoire, H., J. Phys. Chem. 96, 11018 (1992). 8. Attwood, D., Dickinson, N. A., Mosquera, V., and Perez Villar, V., J. Phys. Chem. 91, 4203 (1987). 9. Attwood, D., Blundell, R., Mosquera, V., Garcia, M., and Rodriguez, J., Colloid Polym. Sci. 272, 108 (1994). 10. Attwood, D., Doughty, D., Mosquera, V., and Perez Villar, V., J. Colloid Interface Sci. 141, 316 (1991). 11. Attwood, D., Blundell, R., and Mosquera, V., J. Colloid Interface Sci. 157, 50 (1993).
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12. Mukerjee, P., and Ghosh, A. K., J. Am. Chem. Soc. 1970, 6403. 13. Attwood, D., Mosquera, V., Garcia, M., Suarez, M. J., and Sarmiento, F., J. Colloid Interface Sci. 175, 201 (1995). 14. Shedlovsky, T., J. Am. Chem. Soc. 54, 1411 (1932). 15. Chambers, J. F., Stokes, J. H., and Stokes, R. H., J. Phys. Chem. 60, 985 (1956). 16. Mysels, K. J., and Otter, R., J. Colloid Sci. 16, 462 (1961). 17. Mukerjee, P., and Mysels, K. J., ‘‘Critical Micelle Concentrations of Aqueous Surfactnat Systems.’’ National Bureau of Standards NSRDSNBS36, U.S. Govt. Printing Office, Washington, DC, 1971. 18. Motomura, K., Yamanaka, M., and Aratono, M., Colloid Polym. Sci. 262, 948 (1984). 19. Holland, P. M., and Rubingh, D. N., J. Phys. Chem. 87, 1984 (1983). 20. Nguyen, C. M., Rathman, J. F., and Scamehorn, J. F., J. Colloid Interface Sci. 112, 438 (1986).
coida
AP: Colloid
179, 478–481 (1996)
0240
Micellization in Binary Mixtures of Amphiphilic Drugs DAVID ATTWOOD,*,1 VICTOR MOSQUERA,† LAURA NOVAS,†
AND
FELIX SARMIENTO‡
*Department of Pharmacy, University of Manchester, Manchester M13 9PL, United Kingdom; and †Departamento de Fisica de la Materia Condensada and ‡Departamento de Fisica Aplicada, Facultad de Fisica, Universidad de Santiago, Santiago de Compostela, Spain Received July 19, 1995; accepted October 25, 1995
The composition of the micelles in binary mixtures of the cationic amphiphilic drugs (a) chlorpromazine and promethazine and (b) chlorpromazine and adiphenine has been determined from an analysis of the variation of the critical micelle concentration, as measured by conductivity techniques, as a function of solution composition. Evaluation of the nonideality of mixing of the components of the mixed micelles using a regular solution approximation revealed ideality of mixing in the chlorpromazine/promethazine system. Mixing in the chlorpromazine/adiphenine system did not deviate significantly from ideality despite differences in the structure and packing characteristics of these two drugs. q 1996 Academic Press, Inc.
Key Words: mixed micelles; drugs; critical micelle concentrations.
INTRODUCTION
Several studies on the nonideality of mixing in a wide variety of different surfactant mixtures (see review by Holland (1) have shown a strong influence of the nature of the charge of the two surfactants. Nonideal interactions, as quantified by the dimensionless interaction parameter b, become progressively stronger in going from mixtures of the same surfactant type to those of opposite charge. The magnitude of b has also been reported (1) to be influenced by structural differences between mixed surfactants, for example, by changes in the relative hydrocarbon chain lengths of the two surfactants or changes in the oxyethylene chain length in mixtures involving a nonionic surfactant. In the present study we have examined nonideality of mixing in binary mixtures of amphiphilic drugs. The selected drugs, which are of similar charge (cationic), are either phenothiazine derivatives having rigid, almost planar hydrophobic ring systems (chlorpromazine and promethazine) or are based on the flexible diphenylmethane hydrophobic moiety (adiphenine). The purpose of the study is to identify any differences in nonideality of mixing within micelles composed of the two phenothiazine drugs and those formed by mixtures of a phenothiazine and a diphenylmethane drug. 1
To whom correspondence should be addressed.
478
0021-9797/96 $18.00 Copyright q 1996 by Academic Press, Inc. All rights of reproduction in any form reserved.
AID
JCIS 4116
/
6g0e$$$641
The two types of drug under consideration have different patterns of association. Adiphenine hydrochoride, in common with other diphenylmethane derivatives, associates by a micellar process (2) forming small micelles at a clearly defined critical micelle concentration (cmc). The phenothiazine drugs have been the subject of recent interest due to their unusual association characteristics. Abrupt inflections in the concentration dependence of solution properties in water and dilute aqueous electrolyte were assumed by earlier workers to be indicative of micellar association and the inflections were identified with the cmc of typical surfactants (3, 4). However, recent NMR studies (5) of the change in chemical shift of aromatic protons and C atoms over a wide concentration range in solutions of chlorpromazine in D2O provide evidence for a limited association below this inflection point. Similar conclusions have been drawn from direct measurements (6) of the monomer concentration in aqueous solutions of promethazine using membrane electrodes selective for the cation of this drug and from heat conduction calorimetry (7), osmotic (8) and density (9) studies for aqueous solutions of several phenothiazines. Furthermore, static light scattering and ultrasound velocity measurements have identified additional discontinuities of solution properties at higher solution concentrations. (10, 11). The micellar properties are independent of concentration over the concentration range between the first and second critical concentrations, and NMR studies (5) have suggested offset concaveto-convex vertical stacking of the phenothiazine molecules within the micelles, with alkyl side chains on alternate sides of the stack. Hence, although the self-association of the phenothiazine drugs is by a stacking process similar to that envisaged for the tricyclic dyes (12), the association is not a continuous process as in the dye solutions but is characterised by a series of critical concentrations at which discernible changes in solution properties occur. The first (but not subsequent) of the critical concentrations, which represents the concentration at which stable micellar units are formed, behaves in a similar way to the cmc of typical surfactants when electrolyte is added to the solution; i.e., it decreases in accordance with the predictions of the mass action theory of micellization (11). Similarly,
04-25-96 15:37:56
coida
AP: Colloid
MICELLES IN BINARY MIXTURES OF AMPHIPHILIC DRUGS
FIG. 1. Conductivity, k, as a function of molality, m, for mixtures of chlorpromazine and adiphenine with mole fractions of chlorpromazine of s, 0.00; h, 0.20; n, 0.40; L, 0.50; q, 0.60; l, 0.80; and j, 1.00.
the use of the first critical concentration in calculations of the thermodynamic parameters for micellization gives values which are in agreement with experimentally determined values (13). In this study, the variation of this critical concentration (subsequently referred to as the cmc) with changes in the composition of a binary mixture of the phenothiazine drugs, either together or in combination with adiphenine, has been used to determine the composition of the mixed micelles and the nonideality of mixing within them. EXPERIMENTAL SECTION
Materials. The hydrochlorides of chlorpromazine [2chloro-10-(3-(dimethylamino)propyl)phenothiazine], promethazine [ 10 - ( 2 - ( dimethylamino ) propyl ) phenothiazine ] and adiphenine [2-diethylaminoethyl diphenylacetate] (Sigma Chemical Co.) conformed to the purity requirements of the British Pharmacopoeia and as such contained not less than 98.5% of the specified compound. Conductivity measurements. The conductivity of the binary mixtures was measured at 30 { 0.017C using a specific conductivity meter (Kyoto Electronics, Type C-117). The cell constant was determined with aqueous solutions of KCl over the appropriate concentration range using the molar conductivity data of Shedlovsky (14) and Chambers et al. (15). Water (twice distilled and degassed) was progressively added to concentrated aqueous solutions of chlorpromazine/promethazine and chlorpromazine/adiphenine mixtures of known molality and composition using a peristaltic pump (Dosimat, Model-655, Metrohmn AG) under the control of a Hewlett–Packard Vectra computer. RESULTS AND DISCUSSION
Figure 1 shows conductivity data for mixed systems of chlorpromazine and adiphenine for a range of compositions; similar
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6g0e$$$641
04-25-96 15:37:56
479
FIG. 2. Variation of cmc with composition of the chlorpromazine/promethazine system. Top curve represents the total concentration of free monomeric surfactant against mole fraction of chlorpromazine in mixed micelle, x m2 , as calculated from Eq. [5]. Bottom curve represents the variation of cmc with mole fraction of chlorpromazine in the system, x2 .
plots were obtained for mixtures of chlorpromazine and promethazine. The curvature of these plots in the region of the cmc is not only a consequence of a low aggregation number of the drug micelles but also reflects changes in the composition of the mixed micelles on dilution at concentrations close to the cmc (16). Since there are no clear inflection points in these plots, cmc values were determined from the plots of molal conductivity as a function of (molality)1/2 as recommended by Mysels and Mukerjee (17). The variation of the cmc as a function of the mole fraction of chlorpromazine in both mixed systems is shown in Figs. 2 and 3.
FIG. 3. Variation of cmc with composition of the chlorpromazine/adiphenine system. Top curve represents the total concentration of free monomeric surfactant against mole fraction of chlorpromazine in mixed micelle, x m2 , as calculated from Eq. [5]. Bottom curve represents the variation of cmc with mole fraction of chlorpromazine in the system, x2 .
coida
AP: Colloid
480
ATTWOOD ET AL.
Changes in the distribution of the components of each system between monomeric and micellar phases as a function of the total solution composition were evaluated by analysis of the variation of the cmc with composition using a method proposed by Motomura and co-workers (18) which is based on excess thermodynamic quantities. In this treatment the composition of the mixed micelle formed by surfactants 1 and 2, is derived using the relationship
cmc has enhanced mole fraction in the mixed micelle, as might be expected. An estimation of the nonideality of mixing in the mixed micelles of the two systems was obtained using the simplified approach proposed by Holland and Rubingh (19). In this model the nonideality of mixing of components is quantified using a dimensionless interaction parameter b which may be interpreted as an excess free energy of mixing parameter. According to this model
xV 2m Å xV 2 0 (xV 1 xV 2 /cmc) (Ì cmc/ ÌxV 2 )T,p / [1 0 d dc £1,c £2,d /( £1,c £2 xV 1 / £2,d £1 xV 2 )],
[1]
where cmc Å ( £1 x1 / £2 x2 )cmc
[2]
xV i Å £i xi /( £l xl / £2 x2 ) m i
m i
m 1
(i Å 1, 2) m 2
xV Å £i x /( £1 x / £2 x )
(i Å 1, 2)
[3] [4]
and x1 and x2 are the mole fractions of surfactants 1 and 2 in the binary system; x 1m and x 2m are the mole fractions of surfactants 1 and 2 in the mixed micelle; £1 Å £1,a / £1,c and £2 Å £2,b / £2,d ; £1,a and £1,c are the number of cations and anions produced on dissociation of surfactant 1 and £2,b and £2,d are the number produced on dissociation of surfactant 2. The drugs under investigation are 1:1 electrolytes with identical counterions, i.e., £1,a Å £1,c Å £2,b Å £2,c Å 1 and hence cmc Å 2cmc.
The Kronecker delta, d dc , for systems in which counterions are identical is 1 and hence Eq. [1] reduces to xV 2m Å xV 2 0 2(xV 1 xV 2 /cmc) ( Ìcmc/ ÌxV 2 )T,p .
[5]
The bottom curves of Figs. 2 and 3, showing the variation of the experimentally measured cmc with the composition of the system, were fitted to an equation of the form cmc Å a(xV 2 ) 2 / b(xV 2 ) / c,
[6]
where a, b, and c are constants, thus allowing the precise determination of ( Ìcmc/ Ìx2 )T,p and hence the evaluation of xV 2m as a function of cmc from Eq. [5]. The top lines of Figs. 2 and 3 show the variation of the cmc with the composition of the mixed micelles as determined by this method. Figures 2 and 3 express the relationship between the composition of the micelle and that of the solution in equilibrium with it. The computed (top) curves give the equilibrium total monomeric concentration for a given micellar composition, while the lower curve gives the mole fraction of each component in monomeric form corresponding to this equilibrium. Inspection of these figures shows that the drug with the lower
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04-25-96 15:37:56
bÅ
ln[x2cmc/((1 0 xV 1m ) C *2 )] (xV 1m ) 2
[7]
where C *2 is the cmc of the pure surfactant 2. Values of b of 00.01 and 00.15 were calculated for chlorpromazine/ promethazine and chlorpromazine/adiphenine systems, respectively. Any deviations from ideality ( b Å 0) for these mixtures arise from structural differences of the hydrophobic groups since all three drugs are cationic and fully ionized at the pH of the measurements. In view of the structural similarities between chlorpromazine and promethazine it is not unexpected that their mixing should be an ideal process. In contrast to these phenothiazine drugs, which have rigid, almost planar, hydrophobic systems, adiphenine exhibits flexibility around the central carbon atom of the diphenylmethane moiety. As a consequence, there are differences in the packing modes of these two types of drug within their aggregates. Evidence from recent NMR measurements (5) suggests a convex-to-concave vertical stacking of phenothiazine molecules which is not favored by the more flexible hydrophobes of diphenylmethane derivatives such as adiphenine. The b values calculated for chlorpromazine/adiphenine mixtures, although more negative than those for the mixtures of the phenothiazine drugs, are of similar order of magnitude to those for mixtures of cationic surfactants (for example, mixtures of hexadecyltrimethylammonium chloride and dodecylpyridinium chloride in 0.15 M NaCl have a b value of 00.2 at 307C) (20) suggesting that the structural differences between the two drugs do not lead to any appreciable nonideality of mixing. ACKNOWLEDGMENT The authors thank the Xunta de Galicia for financial support.
REFERENCES 1. Holland, P. M., in ‘‘Mixed Surfactant Systems’’ (P. M. Holland and D. N. Rubingh, Eds.), Chapter 2. ACS Symposium Series 501. Am. Chem. Soc., Washington DC. 1992. 2. Attwood, D., J. Pharm. Pharmacol. 28, 407 (1976). 3. Attwood, D., and Florence, A. T., ‘‘Surfactant Systems,’’ Chapter 4. Chapman & Hall, London, 1983. 4. Attwood, D., Adv. Colloid Interface Sci. 55, 271 (1995).
coida
AP: Colloid
MICELLES IN BINARY MIXTURES OF AMPHIPHILIC DRUGS 5. Attwood, D., Waigh, R. D., Blundell, R., Bloor, D., The´vand, A., Boitard, E., Dube`s, J. P., and Tachoire, H., Mag. Res. Chem. 32, 468 (1994). 6. Wan Bahdi, W., Mwakibete, H., Bloor, D. M., Palepu, R., and WynJones, E., J. Phys. Chem. 96, 918 (1992). 7. Attwood, D., Boitard, E., Dube`s, J. P., and Tachoire, H., J. Phys. Chem. 96, 11018 (1992). 8. Attwood, D., Dickinson, N. A., Mosquera, V., and Perez Villar, V., J. Phys. Chem. 91, 4203 (1987). 9. Attwood, D., Blundell, R., Mosquera, V., Garcia, M., and Rodriguez, J., Colloid Polym. Sci. 272, 108 (1994). 10. Attwood, D., Doughty, D., Mosquera, V., and Perez Villar, V., J. Colloid Interface Sci. 141, 316 (1991). 11. Attwood, D., Blundell, R., and Mosquera, V., J. Colloid Interface Sci. 157, 50 (1993).
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JCIS 4116
/
6g0e$$$641
04-25-96 15:37:56
481
12. Mukerjee, P., and Ghosh, A. K., J. Am. Chem. Soc. 1970, 6403. 13. Attwood, D., Mosquera, V., Garcia, M., Suarez, M. J., and Sarmiento, F., J. Colloid Interface Sci. 175, 201 (1995). 14. Shedlovsky, T., J. Am. Chem. Soc. 54, 1411 (1932). 15. Chambers, J. F., Stokes, J. H., and Stokes, R. H., J. Phys. Chem. 60, 985 (1956). 16. Mysels, K. J., and Otter, R., J. Colloid Sci. 16, 462 (1961). 17. Mukerjee, P., and Mysels, K. J., ‘‘Critical Micelle Concentrations of Aqueous Surfactnat Systems.’’ National Bureau of Standards NSRDSNBS36, U.S. Govt. Printing Office, Washington, DC, 1971. 18. Motomura, K., Yamanaka, M., and Aratono, M., Colloid Polym. Sci. 262, 948 (1984). 19. Holland, P. M., and Rubingh, D. N., J. Phys. Chem. 87, 1984 (1983). 20. Nguyen, C. M., Rathman, J. F., and Scamehorn, J. F., J. Colloid Interface Sci. 112, 438 (1986).
coida
AP: Colloid