- Email: [email protected]
Solubilization of phenolic compounds in nonionic surface-active agents. II. Cloud point and phase changes in solubilization of phenol, cresols, xylenols, and benzoic acid
Solubilization of Phenolic Compounds in Nonionic Surface-Active Agents II. Cloud Point and Phase Changes in Solubilization of Phenol, Cresols, Xylenols, and Benzoic Acid MAX DONBROW AND EMMA AZAZ School of Pharmacy, Hebrew University, Jerusalem, Box 12065, Israel
Received July 25, 1975; accepted January 27, 1976 The cloud point of aqueous polyoxyethylene (24) hexadecanol (cetomacrogol) was depressed by benzoic acid to 44 ° and by phenol, o-, m-, and p-cresols, and the six xylenols to room temperature. The temperature-additive concentration relation was nonlinear and benzoic acid was exceptional in showing two branches. Salt enhanced the depression without changing the form. Concentrations reducing the cloud point to 25 ° are inversely related to hydrophobicity of the phenols. Free and micelle-bound concentrations of the cloud points have been measured in the phenol series and utilized to throw light on the mechanism of clouding.
INTRODUCTION
micellar uptake of solutes below the cloud point (2, 6a, 13). Cloud point fall is also considered due to aggregation number increase, hence the temperature of maximal solubilization is changed in the presence of electrolytes (2, 5). With regard to the effect of solubilizate structure on cloud point, no general theory has yet emerged. Aliphatic hydrocarbons raise the cloud point whereas aromatic hydrocarbons, unsaturated aliphatics and alkanols lower it to some degree but may raise it again at higher concentrations (1, 2, 12). These effects may well be connected with the locus of solubilization, there being four postulated regions for solubilizate incorporation in nonionic micelles (14). Core-solubilization raises the aggregation number to a greater extent than palisade solubilization (5, 8, 15) and might be expected to lower the cloud point. However, core-solubilized materials include the aliphatic hydrocarbons which in fact raise the cloud point (2) or have little effect on it (5). In unsaturated systems, regional distribution of solubilizate may vary with concentration,
The cloud point of a nonionic surfactant is sensitive to additives, which may raise or lower it. The relation between cloud point temperature and additive concentration is nonlinear and highly variable in form in different systems (1, 2). Sometimes the cloud point is depressed to room temperature or below (1), when the Maximum Additive Concentration (M.A.C.) (3) measured by the solubility method could be misleading (4). In most nonionic systems, the M.A.C. increases with temperature rise and some workers believe there is an optimum temperature for maximum uptake (2, 5), thought by Shinoda to be the cloud point itself (6a). Increase in micellar uptake with temperature is believed to result from increase in micellar size (6a, 7, 8). Electrolytes generally lower the cloud point (1, 9, 10), iodides and thiocyanates anomalously raising it, due, it is thought, to opposite effects on the heat of solution (11). Electrolytes increase micellar molecular weight and decrease CMC (7, 8, 12), thereby enhancing 20
Journal of Colloid and Interface Science, Vol. 57, No. 1, October 1976
Copyright ~ 1976 by Academic Press, Inc. All rights of reproduction in any form reserved.
SOLUBILIZATION II reflected in the occurrence of peak aggregation numbers at specific solubilizate-surfactant ratios (15), which could account for concentration dependence of cloud point. Electrolytes and temperature changes would also influence the regional distribution. Evidently, changes in cloud point with concentration are not related simply and solely to aggregation number. Phenolic solutes have been shown to affect the cloud point of cetomacrogol (16) and Triton X-100 (1, 4, 17, 18). Benzoic acid was included in Evans' study (17). Invariably the cloud point of Triton was lowered by phenol concentration increase and raised by concentration increase of the corresponding sodium salts. In view of the exceptionally powerful effects of phenols, a systematic study was undertaken in this work of the effect of phenol, the cresols and the xylenols on the cloud point of cetomacrogol. Benzoic acid was included for comparison. The intention was to study the relationship between hydrophobicity, micellar binding and cloud point lowering effects of the phenols. EXPERIMENTAL
Materials The phenols and cetomacrogol used were described in Part I (33). Benzoic acid was analytical grade (X max 274 nm, e 940) (Mallinckrodt Chemical Works, U. S. A.).
Methods
21 1 - phenol 2 - p.cresol 3-m-cresol - o - cresol 5 - 2,6-xylenol 6-3,5 .....
I00
- -n-
80
o
60
ca.
40
20
I
[
I
0,05
0,1
0.15
Concentration ( H )
FIG. 1. Effect of some phenols on cloud point of cetomacrogol2%. cetomacrogol and 0.005 N HCI at a series of fixed temperatures (50 ml of the solvent was shaken with excess solute until equilibrium was reached, clarified using a filter stick at the temperature of the experiment and the benzoic acid content determined by uv absorption).
Measurement of bound and free concentrations. The potentiometric method described in (33) was used, the total concentrations of the un-ionized phenols being identical to the cloud point concentration at 25°C. RESULTS
Cloud point and phase diagram determinations. The cloud points of cetomacrogol were determined for 2% w/v solutions in the presence of rising total concentration of solutes. Benzoic acid studies were carried out in 0.005 N HCI to suppress ionization. Slow heating and rapid stirring were employed. The sudden turbidity which appeared was reproducible within :t=0.1°C, repeat readings being taken on cooling and reheating. The lower lines in phase diagrams of benzoic acid were determined from measurements of saturation solubility of benzoic acid in 2%
The effect of phenolic compounds on the cloud point of 2O-/ocetomacrogol is shown in Fig. 1 and of benzoic acid in Fig. 2. In the former, the systems contain an isotropic liquid phase to the left of the curves and two phases to their right, one dilute aqueous and the other surfactant-rich. Benzoic acid has two intersecting curves : the upper is a cloud point curve defining regions corresponding to those of the phenol systems. The lower curve has to its right solid benzoic acid in equilibrium with its saturated solution in the aqueous micellar system, while to its left there is isotropic
Journal of CoUoid and Interface Science,
Vol. 57, No. 1, October 1976
22
DONBROW AND AZAZ (average values) for phenol to 28°/0.01 M for 2,5-xylenol. The cloud point depressions in the benzoic acid systems have values near to those of phenol; both cloud point and solubility are decreased progressively on further salt addition.
100
o
70
P D
DISCUSSION
2
Salt Effects
Q. E
The contrast between the nonlinearity of the cloud point curves as a function of phenol or
40-
p - cresol 100
o. cresot
m . cresc
phenot
10-
0
I 0.05
I 0.1
u o
I
60
c
o
Benzoic a c i d concentration(M)
1.0
FIG. 2. Phase diagram of benzoic acid in 2% cetomacrogol and HC1 (0.005 N) at different temperatures and concentrations: (--O--)no electrolyte, (--0--) 0.5 N NaC1. For explanation, see text.
20
005
008
005
008 00S
Concentration
liquid containing solubilized benzoic acid below saturation level. The concentration range which could be studied for each solubilizate was limited, the minimum by the cloud point exceeding the bp and the maximum by the separation of an additional phase. The phenols fall into three groups, viz, xylenols, cresols, and phenol, concentrations increasing with hydrophilicity. The effect of NaC1 is shown in Figs. 3a and 3b. I t invariably lowers the cloud point, about 10% less of each of the phenols being needed to obtain a given cloud point temperature when 0.1 N NaC1 is present. Salt also decreases the cloud point of nonionic surfactants in the absence of solubilizates (1, 10); the decrease is a linear function of NaCI concentration (Fig. 4), amounting to 1.9 ° per 0.1 M increment of NaC1, whereas when the phenols are present, the depression ranges from 3 to 9 ° per 0.1 M increment NaC1. In contrast, the phenols give depressions in the absence of salt ranging from 8.5 ° per 0.01 M increment J o u r n a l o f C o l l o i d a n d I n t e r f a c e Sc i e nc e , Vol. 57, N o . 1, O c t o b e r
A
I
008
P-
007
0.15
( H )
-
100
80 u o 60
L,O
o 2O i L o o
o o
] I' I I o oo
Concentration
(
I I o o
I I , o o
M )
FIG. 3a. Effect of NaC1 on cloud point of cetomacrogol in the presence of phenols. ( 0 - - 0 ) n o NaCl, (O--O) 0.1N NaC1. (b) Effect of NaCI on cloud point of cetomacrogol in the presence of phenols. (O--O) no NaC1, ( 0 - - 0 ) 0.1N NaC1. 1976
SOLUBILIZATION II benzoic acid concentration and the linearity with respect to NaC1 in the absence of the phenols indicates that polar organic substances and inorganic salts do not depress the cloud point by identical mechanisms. This is also borne out by the large differences in the depression per unit concentration increment for the two cases. On the basis of data obtained on the distribution of NaC1 between the two phases present at the cloud point, Doren and Goldfarb argued that the salt effect on the cloud point was exercised at the polyoxyethylene groups, resulting in solubility change and phase separation (11). The "salting-out" effect was studied by Maclay (1) and Schick (10). Schick found that decrease of the lyotropic number of the electrolyte increased the cloud point depression and that the anion effect was dominant. In view of the large excess of water present, the "dehydration" process referred to by these authors may perhaps also involve water-structuring by the anions which is inversely proportional to their lyotropic number (19, 20). The overall entropy decrease and free energy increase caused by structuring is compensated for by increased micellization, which isolates the hydrophobic head group contributing otherwise to waterstructuring (3, 21). Enhancement of micellization results in increase in aggregation number and fall in cloud point. In line with this, decrease in CMC and increase in aggregation number on salt-addition are well known (22). Though the phenols and benzoic acid should also increase water-structuring, their solubilization isotherms show that a major proportion has passed from the water into the micelles (23, 24, 33). Furthermore, salt addition to the solubilizate systems gave depressions two to five times larger than expected for a salt effect. These large depressions would however be accounted for by increased micellar uptake of phenols (33) or benzoic acid (34) if the depression were due predominantly to the influence of the micelle-bound organic solute on micelle properties. Salt increases micellar binding, probably as a result of lowering water
o 'o~
23
90 88 86
.o,.... 1.05 NaCt
r
T
r
1.1
1.15
1.2
concentration
( N )
FIG. 4. Effect of NaC1 concentration on cloud point of 2% cetomacrogol.
solubility of the organic solute and increasing the aggregation number of the surfactant (see Introduction). The lowered M.A.C. of benzoic acid in the presence of salt below the cloud point (Fig. 2), which is in apparent contradiction to the increased micellar binding, evidently stems from water-solubility being the limiting factor which controls the M.A.C. values observed experimentally, discussed in (33).
Cloud-Point and Phase Diagrams The resemblance between the nonlinearities in the solubilization isotherms and the cloud point curves could imply that the sharp fall in cloud point at specific solute concentrations might be due to saturation of the micelles. That saturation is not reached in the case of the phenols is borne out by the difference between the phase diagrams of the phenols and benzoic acid. In benzoic acid, the upper cloud point curve terminates at 44 ° , this being the critical solution temperature for the coexistence of two liquid phases and one solid phase in the ternary system (Fig. 2). The lower curve is the solubility curve of the solid acid in the micellar solution. The large concentration increase with temperature is unlikely to be due to higher micellar uptake since partition coefficients are not highly temperature sensitive (25) but rather to the lowered stability of the crystal lattice of solids at higher temperatures (6b, 26). Extrapolation of the two curves defines a fourth region, enclosed by them, shown schematically in Fig. 5 (a), which contains all three phases in varying amounts. Such regions have
Journal of Colloid and Interface Science, Vol. 57, N o . 1, O c t o b e r 1976
24
DONBROW AND AZAZ of this type in the phase diagrams of the solid xylenols and their nonappearance must be due to the enhanced cloud point depressions. There is no evidence from the cloud point curves that micelle-saturation analogous to that observed in benzoic acid occurs in any of the phenol systems.
100
ill
IV
Cloud Point and Solute Binding
Bl ~C TOTAL SOLUBILIZATE CONCENTRATION
FIG. 5. Phase diagrams (schematic) of solubilizatenonionic surfactant systems as a function of solubilizate concentration and temperature. Surfactant concentration constant. AB = cloud point curve, CD = solubility curve of solubilizate in micelle. I. One phase (isotropic micellarsolution) II. Two phases (I + excess solubilizate), III. Two phases (surfactant-rich containing solubilizate and some water + dilute aqueous) IV. Three phases (as in III + excesssolubilizate). been detected in analogous systems (5) and are characterized under isothermal conditions (27). The absence of the lower curve in the phenol phase diagrams (Figs. 1 and 3) is evidently due to their much higher solubility in water. The hypothetical solubility curve would lie to the right of the cloud point curve (Fig. 5(b)) and would be difficult to measure experimentally except at low temperatures for solutes which separate as a crystalline phase. One would have expected to see solubility curves methy
l.
group
2 2 3 6 /, 5
423
positions
2 5
3 4
J
100
o_
i
,, ,
,
,
lit
~
i
"*
i
, i
,
r
! ji
r i i t t i
•--
i
Q"
r
i
i ,
2O
I 0.05
l 0.1
I 0.15
I 0.2
Ko
F I G . 6. R e l a t i o n b e t w e e n c l o u d p o i n t a n d K 0 v a l u e s f o r p h e n o l a n d its h o m o l o g u e s a t 0 . 0 5 M c o n c e n t r a t i o n in 2 % c e t o m a c r o g o l .
From the magnitude of the cloud point fall in relation to the concentrations of the phenols, it would appear that separation of the micellar phase at room temperature resulted from either a specific phenol effect or a general phenomenon occurring to a greater degree with phenols than with other solubilizates. Such a general effect could be the increase in aggregation number with increased solubilization, which has been reported both prior to saturation in core-solubilized systems (15), and at high solubilizate ratios in palisade-solubilized systems (8, 28). However, in no case has the effect been found to be as strong as in the phenols, notwithstanding that neither of the two phenolic substances included in previous studies, p-hydroxybenzoic acid and ethyl phydroxybenzoate, were found to increase micellar-aggregation. Nevertheless, the hydrophilicity of the phenols might well be a factor, as noted in the Results. This is supported by the relationship between cloud point temperature at 0.05 M total phenol concentration and the micellar binding constant of each of the phenols as defined in (33) (Fig. 6). In view of the multiplicity of factors involved in evaluating solubilizate distribution at different temperatures, where the degree of hydration and the aggregation number of the surfactant are unknown variables (8), comparisons of the phenol effects will be made under isothermal conditions. The phenol concentrations which lower the cloud point to 25 ° are related to the micellar binding constants (Fig. 7) but not linearly, approaching a limiting concentration value of about 0.05 M at high K0 values and curving towards infinity at low values. This would be
Journal of Colloid and Interface Science, Vol. 57, No. 1, October 1976
SOLUBILIZATION II
expected if the micelle-bound phenol were the determining factor. Bound and free concentrations were consequently evaluated by direct measurement at the experimental concentrations which gave a cloud point at 25 ° using the potentiometric procedure previously described (33). Since equal concentrations of the respective sodium phenates were present in this technique, an estimate was made of their possible effects on the bound concentrations. Observation of the cloud point of 2% cetomacrogol in NaC1 on addition of sodium phenate showed that the depressions were less than those given by equivalent increments of NaC1. If the phenate effect were equivalent to that of NaC1,1 the change in the bound concentration would be about 6% for phenol and very small (<3%) in the other phenols. Original and adjusted values are included in Table I. A plot of bound against free concentration (Fig. 8) of various phenols estimated using the concentrations which gave 25 ° cloud points includes five points near to a straight line with intercept at 0.037 M (2.24 mole/mole cetomacrogol) of bound phenol3 In the higher homologues of low water solubility, the bound concentrations represent the major part of the total phenol present. It would thus seem that cloud point is a function of the bound concentration, though free aqueous concentrations ]night influence micelle properties in the more water-soluble phenols. The effect on the cloud point of increase in the solubilizate concentration resembles closely the effect of reduction in the number of EO units in the POE chain of nonionic surfactants containing a constant lipophilic group (29, 30). This suggests that the mechanism may be reThe percentage difference in phenol concentration at the 25 ° cloud point in the presence and absence of 0.I N NaC1 is known for each of the phenols (see Fig. 3). F r o m this, the effect of other salt concentrations was calculated assuming proportionality; concentrations used were the experimental phenate values. Tri- and tetra-methyl homologues of phenol accord with this p a t t e r n (Azaz, Donbrow, and Rafaelovitz, unpublished results).
25 methyl.
group positions 2 23 3 2 6
0.15
~i,
&
O. 10
4
3
:I
;
1
E i
i ,
i i
i J
, ,
r
i
r
J
i J
i
,
E
:
i1[ lit
5
i
i i
J
, i
'J J
I
1
\
0.05
f
I
0.05
0.1
I
0.15
r
02 Ko
FIo. 7. Relation between total concentrations of phenols reducing cloud point of cetomacrogol solution to 25°C and K0 values.
duction in the hydrophilicity of the EO chain due to phenol binding. In fact, partition coefficient relationships (33) and uv studies indicate that the phenols are present mainly in the palisade region (Part III, to appear). Kabadi and Hammerlund have shown that phenols form complexes with PEG in aqueous solutions which at high phenol concentrations separate out as oily drops (31). In the hexadecanol series of surfactants, a plot of Schott's TABLE I Bound and Free Phenol and N u m b e r of EO units Blocked at Phenol Concentrations Reducing Cloud Point to 25°C Compound
Phenol 2-Cresol 3-Cresol 3.4-Xylenoi 3.5-Xylenol 2.3-Xylenol 2.5-Xylenol
Free Bound phenol Blocked EO a phenol (units/mole (mM) (mM)a (mole/ (mole/ phenol) moleb) mole c) 76.6 32.0 37.0 16.3 12.7 11.0 17.4
73.4 46.4 45.5 42.7 41.3 39.8 33.6
4.44 2.81 2.75 2.88 2.50 2.41 2.03
4.17 2.78 2.66 2.54 2.42 2.36 2.00
3.83 c 5.75 6.01 6.30 6.61 6.78 8.00
In 2% cetomacrogol solution. b Calculated on total cetomacrogol (mol wt 1210, C M C very low) from values in Column 3. c As in footnote b, corrected for sodium phenate effects (see text). d Calculated for 22 EO u n i t s / m o l e cetomacrogol assuming 6 EO units are free of phenol molecules.
Journal of Colloid and Interface Science, Vol. 57, No, 1, October 1976
26
DONBROW AND AZAZ
cresols, 2,3-, 2,4-, 3,4-xylenols; 8.4 A for 2,5-, 2,6-, 3,5-xylenols) they do not accord with the o blocking of six to eight units per phenol mole0.06 o. o cule and do not correlate with the concentra,, &3 ~ tion sequence of the isomers. Evidently, the o 0.04 increasing effectiveness of the higher homo2 I 1DI I I I I I I logues in lowering cloud point is not fully ac0.02 0.04 0.06 frO8 counted for by a simple dimensional treatment. Free phenot M Bearing in mind the correlation of cloud FIG. 8. Relation between free and bound concentra- point with micellar binding constants (Fig. 7) tions of differentphenolsin 2% cetomacrogolsolutions. and the evidence presented in Parts I and III ~7 uncorrected q) corrected for salt effect. Numbers of this series, the most probable explanation is represent methyl group positions. P = phenol. that the solubilizate molecules are present in the palisade region of the surfactant and exert data (29) indicates that cloud point tempera- a water-structuring effect on the surrounding tures of 75 and 25°C are given by nonionic envelope of solvent molecules, which would surfactants containing about nine and six free reduce the solvation and water-solubility of EO groups, respectively. As a first approxima- the EO units in their vicinity. In general, the tion, the parallelism of the phenol effect will strength of this effect would be related to the be considered by assuming that when the hydrophobicity of the phenols, but specific cloud point is reduced to 25 °, six EO units localized water-structuring effects would differ per molecule of cetomacrogol remain free and from isomer to isomer. In effect, the powerful influence of phenols water-solvated, while the other 16 units are blocked by the bound phenol in a way which on cloud point would result from a combinaeffectively neutralizes their influence on the tion of hydrogen bonding, favoring retention micelle properties. The number of EO units of these molecules in the ethylene oxide region blocked per phenol molecule bound, calculated of the micelles, together with water-structuring on this basis, is listed in Table I. Values range exercised by solubilizate molecules in this enfrom about 3.8 in phenol to 8.0 in 2,5-xylenol. vironment. This is in contrast to the more The length of a phenol molecule measured common situation of nonhydrogen bonding or through the oxygen-aromatic ring axis using weak hydrogen bonding molecules, in which Courtauld models is 7.7 A and its breadth is water-structuring would favor their transfer 6.3 A. The oxygen-oxygen distance in an EO to the micelle core, analogous to the formation chain arranged in the meander conformation of a hydrophobic bond. is 3.8 A (32) hence a phenol molecule H-bonded to oxygen and with its ring plane parallel to SUMMARY the EO chain axis could feasibly interfere with (1) The cloud point of aqueous cetomacrogol hydration of two to three EO units along its molecular length and possibly an additional is depressed steeply by increase in concentraone across its width, so that the 3.6 ratio value tion of phenol, cresols, or xylenols to below is not unreasonable. In the zig-zag conforma- room temperature. In the case of benzoic acid tion however, the EO chain is more extended the cloud point curve meets the solubilization curve at 44 °, which is the minimum cloud and fewer units would be blocked. With regard to the cresols and xylenols, al- point. (2) Salt depresses the cloud point and lowers though the dimensions are greater (length through oxygen-ring axis: p-methyl com- the solute concentrations required for phase pounds, ca. 8.6 A; maximum breadth, perpen- separation, due mainly to its effects on micellar dicular to oxygen-ring axis: 7.35 A for o-, m- binding. 5
0.08
'5'
Journal of Colloid and Interface Science,
Vp
V o l . 57, N o . 1, O c t o b e r 1 9 7 6
SOLUBILIZATION II
(3) The effect of a phenol on cloud point is inversely related to its hydrophobicity. (4) Concentrations needed to reduce the cloud point to 25 ° fall towards a limiting value of ca. 2.24 mole bound phenol/mole surfactant for the most lipophilic homologues, free concentrations falling to very low values. The mechanism is discussed. ACKNOWLEDGMENTS The authors are grateful to Mrs. P. Fischer and Mr. Y. Peres for their technical assistance. Some of this work formed part of a thesis submitted by E. Azaz to the Hebrew University of Jerusalem for the Ph.D. degree. REFERENCES 1. MACLAY,W. N., J. Colloid Sei. 11, 272-285 (1956). 2. SAITO,H. ANDSHINODA,K., J. Colloid Interface Sci. 24, 10-15 (1967). 3. ELWORTHY, P. H., FLORENCE, A. T., AND MACFARLANE, C. B., "Solubilization by SurfaceActive Agents and its Application in Chemistry and Biological Sciences," Chapman and Hall, London, 1968. 4. WEIDEN, M. H. J. AND NORTON, L. B., J. Colloid Sci. 8, 606-610 (1953). 5. NAKAGAWA,T. AND TORI, K., Kolloid Z. 168, 132139 (1960). 6. SHINODA,K., in "Solvent Properties of Surfactant Solutions," (Shinoda, Ed.), (a) p. 27, (b) p. 11. Marcel Dekker, New York, 1967. 7. BAL~BRA, R. R., CLUNIE, J. S., CORKILL, J. M., AND GOODMAN,J. F., Trans. Faraday Soc. 58, 1661 (1962). 8. NAKAGAWA,T., KURYAMA,K., AND INONUE, H., J. Colloid Sci. 15, 268-277 (1950). 9. ARAI, H., Y. Colloid Interface Sci. 53, 348-351 (1967). i0. SCmCK, M. J., J. Colloid Sci. 17, 801-813 (1962). 11. DOREN, A. AND GOLDFARB,J., J. Colloid Interface Sci. 32, 67-72 (1970).
27
12. NAKAGAWA,T., in "Nonionic Surfactants," p. 558. (Schick, Ed.) Marcel Dekker, New York, 1967. 13. MANXOWICH,A. M., Ind. Eng. Chem. 47, 2175-2181 (1955). 14. RIEGEL~N, S., ALLAWALA,N. A., Hg.ENOFF, M. K., ANDSTRAIT,L. A., J. Colloid Sci. 13, 208-217 (1958). 15. ATTWOOD,D., ELWORTHY,P. H., AND KAYNE, S. B., J. Pharm. Pharmacol. 23, 77S-84S (1971). 16. HADGRAFT,J. W., J. Pharm. Pharmacol. 6, 816829 (1954). 17. EVANS, W. P., J. Pharm. Pharmacol. 16, 323-331 (1964). 18. LIVINGSTON, H. K., J. Colloid Sci. 9, 365-368 (1954). 19. FRANK,H. S. ANDEVANS, M. W., J. Chem. Physics 13, 507 (1945). 20. ROBINSON,R. A. AND STOKES,R. H., "Electrolyte Solutions," 2nd ed. Butterworths, London, 1959. 21. WISHmA, A., J. Phys. Chem. 67, 2079-2082 (1963). 22. MUKERJEE, P., Advan. Colloid Interface Sei. 1, 241-275 (1967). 23. DONBROW,M., MOLYNEUX,P., ANDRHODES, C. T., J. Chem. Soc. (A), 561-565 (1967). 24. DONBROW,M. AND RHODES, C. T., J. Chem. Soe., Supplement 2, 6166-6171 (1964). 25. LEO, A., HANSCH, C., AND ELKINS, D., Chem. Rev. 71, 525-616 (1971). 26. WINsoa, P. A., "Solvent Properties of Amphiphilic Compounds," p. 135, Butterworths, London, 1954. 27. MULLEY, B. A. in "Advances in Pharmaceutical Sciences," Vol. 1, p. 145. (Bean, Beckett, and Carless, Eds.), Academic Press, New York, 1964. 28. KURIYAMA,K., Kolloid Z. 180, 55 (1962). 29. SCHOTT,H., J. Pharm. Sci. 58, 1443-1449 (1969). 30. DONBROW, M., HAMBURGER, R., AND AZAZ, E., Y. Pharm. Pharmacol. 27, 160-166 (1975). 31. KABADI,B. N. ANDHAM_MERLUND,E. R., J. Pharm. Sci. 55, 1069-1076 (1966). 32. ROSCH, M., in "Nonionic Surfactants," p. 753. (Schick, Ed.), Marcel Dekker, New York, 1967. 33. AzAz, E. AND DONBROW, M., J. Colloid Interface Sci. 56, (1976). (Part I of this article). 34. AzAz, E. AND DONBROW,M., unpublished data.
Journal of Colloid and Interface Science, Vol. 57. No. 1, October 1976
Received July 25, 1975; accepted January 27, 1976 The cloud point of aqueous polyoxyethylene (24) hexadecanol (cetomacrogol) was depressed by benzoic acid to 44 ° and by phenol, o-, m-, and p-cresols, and the six xylenols to room temperature. The temperature-additive concentration relation was nonlinear and benzoic acid was exceptional in showing two branches. Salt enhanced the depression without changing the form. Concentrations reducing the cloud point to 25 ° are inversely related to hydrophobicity of the phenols. Free and micelle-bound concentrations of the cloud points have been measured in the phenol series and utilized to throw light on the mechanism of clouding.
INTRODUCTION
micellar uptake of solutes below the cloud point (2, 6a, 13). Cloud point fall is also considered due to aggregation number increase, hence the temperature of maximal solubilization is changed in the presence of electrolytes (2, 5). With regard to the effect of solubilizate structure on cloud point, no general theory has yet emerged. Aliphatic hydrocarbons raise the cloud point whereas aromatic hydrocarbons, unsaturated aliphatics and alkanols lower it to some degree but may raise it again at higher concentrations (1, 2, 12). These effects may well be connected with the locus of solubilization, there being four postulated regions for solubilizate incorporation in nonionic micelles (14). Core-solubilization raises the aggregation number to a greater extent than palisade solubilization (5, 8, 15) and might be expected to lower the cloud point. However, core-solubilized materials include the aliphatic hydrocarbons which in fact raise the cloud point (2) or have little effect on it (5). In unsaturated systems, regional distribution of solubilizate may vary with concentration,
The cloud point of a nonionic surfactant is sensitive to additives, which may raise or lower it. The relation between cloud point temperature and additive concentration is nonlinear and highly variable in form in different systems (1, 2). Sometimes the cloud point is depressed to room temperature or below (1), when the Maximum Additive Concentration (M.A.C.) (3) measured by the solubility method could be misleading (4). In most nonionic systems, the M.A.C. increases with temperature rise and some workers believe there is an optimum temperature for maximum uptake (2, 5), thought by Shinoda to be the cloud point itself (6a). Increase in micellar uptake with temperature is believed to result from increase in micellar size (6a, 7, 8). Electrolytes generally lower the cloud point (1, 9, 10), iodides and thiocyanates anomalously raising it, due, it is thought, to opposite effects on the heat of solution (11). Electrolytes increase micellar molecular weight and decrease CMC (7, 8, 12), thereby enhancing 20
Journal of Colloid and Interface Science, Vol. 57, No. 1, October 1976
Copyright ~ 1976 by Academic Press, Inc. All rights of reproduction in any form reserved.
SOLUBILIZATION II reflected in the occurrence of peak aggregation numbers at specific solubilizate-surfactant ratios (15), which could account for concentration dependence of cloud point. Electrolytes and temperature changes would also influence the regional distribution. Evidently, changes in cloud point with concentration are not related simply and solely to aggregation number. Phenolic solutes have been shown to affect the cloud point of cetomacrogol (16) and Triton X-100 (1, 4, 17, 18). Benzoic acid was included in Evans' study (17). Invariably the cloud point of Triton was lowered by phenol concentration increase and raised by concentration increase of the corresponding sodium salts. In view of the exceptionally powerful effects of phenols, a systematic study was undertaken in this work of the effect of phenol, the cresols and the xylenols on the cloud point of cetomacrogol. Benzoic acid was included for comparison. The intention was to study the relationship between hydrophobicity, micellar binding and cloud point lowering effects of the phenols. EXPERIMENTAL
Materials The phenols and cetomacrogol used were described in Part I (33). Benzoic acid was analytical grade (X max 274 nm, e 940) (Mallinckrodt Chemical Works, U. S. A.).
Methods
21 1 - phenol 2 - p.cresol 3-m-cresol - o - cresol 5 - 2,6-xylenol 6-3,5 .....
I00
- -n-
80
o
60
ca.
40
20
I
[
I
0,05
0,1
0.15
Concentration ( H )
FIG. 1. Effect of some phenols on cloud point of cetomacrogol2%. cetomacrogol and 0.005 N HCI at a series of fixed temperatures (50 ml of the solvent was shaken with excess solute until equilibrium was reached, clarified using a filter stick at the temperature of the experiment and the benzoic acid content determined by uv absorption).
Measurement of bound and free concentrations. The potentiometric method described in (33) was used, the total concentrations of the un-ionized phenols being identical to the cloud point concentration at 25°C. RESULTS
Cloud point and phase diagram determinations. The cloud points of cetomacrogol were determined for 2% w/v solutions in the presence of rising total concentration of solutes. Benzoic acid studies were carried out in 0.005 N HCI to suppress ionization. Slow heating and rapid stirring were employed. The sudden turbidity which appeared was reproducible within :t=0.1°C, repeat readings being taken on cooling and reheating. The lower lines in phase diagrams of benzoic acid were determined from measurements of saturation solubility of benzoic acid in 2%
The effect of phenolic compounds on the cloud point of 2O-/ocetomacrogol is shown in Fig. 1 and of benzoic acid in Fig. 2. In the former, the systems contain an isotropic liquid phase to the left of the curves and two phases to their right, one dilute aqueous and the other surfactant-rich. Benzoic acid has two intersecting curves : the upper is a cloud point curve defining regions corresponding to those of the phenol systems. The lower curve has to its right solid benzoic acid in equilibrium with its saturated solution in the aqueous micellar system, while to its left there is isotropic
Journal of CoUoid and Interface Science,
Vol. 57, No. 1, October 1976
22
DONBROW AND AZAZ (average values) for phenol to 28°/0.01 M for 2,5-xylenol. The cloud point depressions in the benzoic acid systems have values near to those of phenol; both cloud point and solubility are decreased progressively on further salt addition.
100
o
70
P D
DISCUSSION
2
Salt Effects
Q. E
The contrast between the nonlinearity of the cloud point curves as a function of phenol or
40-
p - cresol 100
o. cresot
m . cresc
phenot
10-
0
I 0.05
I 0.1
u o
I
60
c
o
Benzoic a c i d concentration(M)
1.0
FIG. 2. Phase diagram of benzoic acid in 2% cetomacrogol and HC1 (0.005 N) at different temperatures and concentrations: (--O--)no electrolyte, (--0--) 0.5 N NaC1. For explanation, see text.
20
005
008
005
008 00S
Concentration
liquid containing solubilized benzoic acid below saturation level. The concentration range which could be studied for each solubilizate was limited, the minimum by the cloud point exceeding the bp and the maximum by the separation of an additional phase. The phenols fall into three groups, viz, xylenols, cresols, and phenol, concentrations increasing with hydrophilicity. The effect of NaC1 is shown in Figs. 3a and 3b. I t invariably lowers the cloud point, about 10% less of each of the phenols being needed to obtain a given cloud point temperature when 0.1 N NaC1 is present. Salt also decreases the cloud point of nonionic surfactants in the absence of solubilizates (1, 10); the decrease is a linear function of NaCI concentration (Fig. 4), amounting to 1.9 ° per 0.1 M increment of NaC1, whereas when the phenols are present, the depression ranges from 3 to 9 ° per 0.1 M increment NaC1. In contrast, the phenols give depressions in the absence of salt ranging from 8.5 ° per 0.01 M increment J o u r n a l o f C o l l o i d a n d I n t e r f a c e Sc i e nc e , Vol. 57, N o . 1, O c t o b e r
A
I
008
P-
007
0.15
( H )
-
100
80 u o 60
L,O
o 2O i L o o
o o
] I' I I o oo
Concentration
(
I I o o
I I , o o
M )
FIG. 3a. Effect of NaC1 on cloud point of cetomacrogol in the presence of phenols. ( 0 - - 0 ) n o NaCl, (O--O) 0.1N NaC1. (b) Effect of NaCI on cloud point of cetomacrogol in the presence of phenols. (O--O) no NaC1, ( 0 - - 0 ) 0.1N NaC1. 1976
SOLUBILIZATION II benzoic acid concentration and the linearity with respect to NaC1 in the absence of the phenols indicates that polar organic substances and inorganic salts do not depress the cloud point by identical mechanisms. This is also borne out by the large differences in the depression per unit concentration increment for the two cases. On the basis of data obtained on the distribution of NaC1 between the two phases present at the cloud point, Doren and Goldfarb argued that the salt effect on the cloud point was exercised at the polyoxyethylene groups, resulting in solubility change and phase separation (11). The "salting-out" effect was studied by Maclay (1) and Schick (10). Schick found that decrease of the lyotropic number of the electrolyte increased the cloud point depression and that the anion effect was dominant. In view of the large excess of water present, the "dehydration" process referred to by these authors may perhaps also involve water-structuring by the anions which is inversely proportional to their lyotropic number (19, 20). The overall entropy decrease and free energy increase caused by structuring is compensated for by increased micellization, which isolates the hydrophobic head group contributing otherwise to waterstructuring (3, 21). Enhancement of micellization results in increase in aggregation number and fall in cloud point. In line with this, decrease in CMC and increase in aggregation number on salt-addition are well known (22). Though the phenols and benzoic acid should also increase water-structuring, their solubilization isotherms show that a major proportion has passed from the water into the micelles (23, 24, 33). Furthermore, salt addition to the solubilizate systems gave depressions two to five times larger than expected for a salt effect. These large depressions would however be accounted for by increased micellar uptake of phenols (33) or benzoic acid (34) if the depression were due predominantly to the influence of the micelle-bound organic solute on micelle properties. Salt increases micellar binding, probably as a result of lowering water
o 'o~
23
90 88 86
.o,.... 1.05 NaCt
r
T
r
1.1
1.15
1.2
concentration
( N )
FIG. 4. Effect of NaC1 concentration on cloud point of 2% cetomacrogol.
solubility of the organic solute and increasing the aggregation number of the surfactant (see Introduction). The lowered M.A.C. of benzoic acid in the presence of salt below the cloud point (Fig. 2), which is in apparent contradiction to the increased micellar binding, evidently stems from water-solubility being the limiting factor which controls the M.A.C. values observed experimentally, discussed in (33).
Cloud-Point and Phase Diagrams The resemblance between the nonlinearities in the solubilization isotherms and the cloud point curves could imply that the sharp fall in cloud point at specific solute concentrations might be due to saturation of the micelles. That saturation is not reached in the case of the phenols is borne out by the difference between the phase diagrams of the phenols and benzoic acid. In benzoic acid, the upper cloud point curve terminates at 44 ° , this being the critical solution temperature for the coexistence of two liquid phases and one solid phase in the ternary system (Fig. 2). The lower curve is the solubility curve of the solid acid in the micellar solution. The large concentration increase with temperature is unlikely to be due to higher micellar uptake since partition coefficients are not highly temperature sensitive (25) but rather to the lowered stability of the crystal lattice of solids at higher temperatures (6b, 26). Extrapolation of the two curves defines a fourth region, enclosed by them, shown schematically in Fig. 5 (a), which contains all three phases in varying amounts. Such regions have
Journal of Colloid and Interface Science, Vol. 57, N o . 1, O c t o b e r 1976
24
DONBROW AND AZAZ of this type in the phase diagrams of the solid xylenols and their nonappearance must be due to the enhanced cloud point depressions. There is no evidence from the cloud point curves that micelle-saturation analogous to that observed in benzoic acid occurs in any of the phenol systems.
100
ill
IV
Cloud Point and Solute Binding
Bl ~C TOTAL SOLUBILIZATE CONCENTRATION
FIG. 5. Phase diagrams (schematic) of solubilizatenonionic surfactant systems as a function of solubilizate concentration and temperature. Surfactant concentration constant. AB = cloud point curve, CD = solubility curve of solubilizate in micelle. I. One phase (isotropic micellarsolution) II. Two phases (I + excess solubilizate), III. Two phases (surfactant-rich containing solubilizate and some water + dilute aqueous) IV. Three phases (as in III + excesssolubilizate). been detected in analogous systems (5) and are characterized under isothermal conditions (27). The absence of the lower curve in the phenol phase diagrams (Figs. 1 and 3) is evidently due to their much higher solubility in water. The hypothetical solubility curve would lie to the right of the cloud point curve (Fig. 5(b)) and would be difficult to measure experimentally except at low temperatures for solutes which separate as a crystalline phase. One would have expected to see solubility curves methy
l.
group
2 2 3 6 /, 5
423
positions
2 5
3 4
J
100
o_
i
,, ,
,
,
lit
~
i
"*
i
, i
,
r
! ji
r i i t t i
•--
i
Q"
r
i
i ,
2O
I 0.05
l 0.1
I 0.15
I 0.2
Ko
F I G . 6. R e l a t i o n b e t w e e n c l o u d p o i n t a n d K 0 v a l u e s f o r p h e n o l a n d its h o m o l o g u e s a t 0 . 0 5 M c o n c e n t r a t i o n in 2 % c e t o m a c r o g o l .
From the magnitude of the cloud point fall in relation to the concentrations of the phenols, it would appear that separation of the micellar phase at room temperature resulted from either a specific phenol effect or a general phenomenon occurring to a greater degree with phenols than with other solubilizates. Such a general effect could be the increase in aggregation number with increased solubilization, which has been reported both prior to saturation in core-solubilized systems (15), and at high solubilizate ratios in palisade-solubilized systems (8, 28). However, in no case has the effect been found to be as strong as in the phenols, notwithstanding that neither of the two phenolic substances included in previous studies, p-hydroxybenzoic acid and ethyl phydroxybenzoate, were found to increase micellar-aggregation. Nevertheless, the hydrophilicity of the phenols might well be a factor, as noted in the Results. This is supported by the relationship between cloud point temperature at 0.05 M total phenol concentration and the micellar binding constant of each of the phenols as defined in (33) (Fig. 6). In view of the multiplicity of factors involved in evaluating solubilizate distribution at different temperatures, where the degree of hydration and the aggregation number of the surfactant are unknown variables (8), comparisons of the phenol effects will be made under isothermal conditions. The phenol concentrations which lower the cloud point to 25 ° are related to the micellar binding constants (Fig. 7) but not linearly, approaching a limiting concentration value of about 0.05 M at high K0 values and curving towards infinity at low values. This would be
Journal of Colloid and Interface Science, Vol. 57, No. 1, October 1976
SOLUBILIZATION II
expected if the micelle-bound phenol were the determining factor. Bound and free concentrations were consequently evaluated by direct measurement at the experimental concentrations which gave a cloud point at 25 ° using the potentiometric procedure previously described (33). Since equal concentrations of the respective sodium phenates were present in this technique, an estimate was made of their possible effects on the bound concentrations. Observation of the cloud point of 2% cetomacrogol in NaC1 on addition of sodium phenate showed that the depressions were less than those given by equivalent increments of NaC1. If the phenate effect were equivalent to that of NaC1,1 the change in the bound concentration would be about 6% for phenol and very small (<3%) in the other phenols. Original and adjusted values are included in Table I. A plot of bound against free concentration (Fig. 8) of various phenols estimated using the concentrations which gave 25 ° cloud points includes five points near to a straight line with intercept at 0.037 M (2.24 mole/mole cetomacrogol) of bound phenol3 In the higher homologues of low water solubility, the bound concentrations represent the major part of the total phenol present. It would thus seem that cloud point is a function of the bound concentration, though free aqueous concentrations ]night influence micelle properties in the more water-soluble phenols. The effect on the cloud point of increase in the solubilizate concentration resembles closely the effect of reduction in the number of EO units in the POE chain of nonionic surfactants containing a constant lipophilic group (29, 30). This suggests that the mechanism may be reThe percentage difference in phenol concentration at the 25 ° cloud point in the presence and absence of 0.I N NaC1 is known for each of the phenols (see Fig. 3). F r o m this, the effect of other salt concentrations was calculated assuming proportionality; concentrations used were the experimental phenate values. Tri- and tetra-methyl homologues of phenol accord with this p a t t e r n (Azaz, Donbrow, and Rafaelovitz, unpublished results).
25 methyl.
group positions 2 23 3 2 6
0.15
~i,
&
O. 10
4
3
:I
;
1
E i
i ,
i i
i J
, ,
r
i
r
J
i J
i
,
E
:
i1[ lit
5
i
i i
J
, i
'J J
I
1
\
0.05
f
I
0.05
0.1
I
0.15
r
02 Ko
FIo. 7. Relation between total concentrations of phenols reducing cloud point of cetomacrogol solution to 25°C and K0 values.
duction in the hydrophilicity of the EO chain due to phenol binding. In fact, partition coefficient relationships (33) and uv studies indicate that the phenols are present mainly in the palisade region (Part III, to appear). Kabadi and Hammerlund have shown that phenols form complexes with PEG in aqueous solutions which at high phenol concentrations separate out as oily drops (31). In the hexadecanol series of surfactants, a plot of Schott's TABLE I Bound and Free Phenol and N u m b e r of EO units Blocked at Phenol Concentrations Reducing Cloud Point to 25°C Compound
Phenol 2-Cresol 3-Cresol 3.4-Xylenoi 3.5-Xylenol 2.3-Xylenol 2.5-Xylenol
Free Bound phenol Blocked EO a phenol (units/mole (mM) (mM)a (mole/ (mole/ phenol) moleb) mole c) 76.6 32.0 37.0 16.3 12.7 11.0 17.4
73.4 46.4 45.5 42.7 41.3 39.8 33.6
4.44 2.81 2.75 2.88 2.50 2.41 2.03
4.17 2.78 2.66 2.54 2.42 2.36 2.00
3.83 c 5.75 6.01 6.30 6.61 6.78 8.00
In 2% cetomacrogol solution. b Calculated on total cetomacrogol (mol wt 1210, C M C very low) from values in Column 3. c As in footnote b, corrected for sodium phenate effects (see text). d Calculated for 22 EO u n i t s / m o l e cetomacrogol assuming 6 EO units are free of phenol molecules.
Journal of Colloid and Interface Science, Vol. 57, No, 1, October 1976
26
DONBROW AND AZAZ
cresols, 2,3-, 2,4-, 3,4-xylenols; 8.4 A for 2,5-, 2,6-, 3,5-xylenols) they do not accord with the o blocking of six to eight units per phenol mole0.06 o. o cule and do not correlate with the concentra,, &3 ~ tion sequence of the isomers. Evidently, the o 0.04 increasing effectiveness of the higher homo2 I 1DI I I I I I I logues in lowering cloud point is not fully ac0.02 0.04 0.06 frO8 counted for by a simple dimensional treatment. Free phenot M Bearing in mind the correlation of cloud FIG. 8. Relation between free and bound concentra- point with micellar binding constants (Fig. 7) tions of differentphenolsin 2% cetomacrogolsolutions. and the evidence presented in Parts I and III ~7 uncorrected q) corrected for salt effect. Numbers of this series, the most probable explanation is represent methyl group positions. P = phenol. that the solubilizate molecules are present in the palisade region of the surfactant and exert data (29) indicates that cloud point tempera- a water-structuring effect on the surrounding tures of 75 and 25°C are given by nonionic envelope of solvent molecules, which would surfactants containing about nine and six free reduce the solvation and water-solubility of EO groups, respectively. As a first approxima- the EO units in their vicinity. In general, the tion, the parallelism of the phenol effect will strength of this effect would be related to the be considered by assuming that when the hydrophobicity of the phenols, but specific cloud point is reduced to 25 °, six EO units localized water-structuring effects would differ per molecule of cetomacrogol remain free and from isomer to isomer. In effect, the powerful influence of phenols water-solvated, while the other 16 units are blocked by the bound phenol in a way which on cloud point would result from a combinaeffectively neutralizes their influence on the tion of hydrogen bonding, favoring retention micelle properties. The number of EO units of these molecules in the ethylene oxide region blocked per phenol molecule bound, calculated of the micelles, together with water-structuring on this basis, is listed in Table I. Values range exercised by solubilizate molecules in this enfrom about 3.8 in phenol to 8.0 in 2,5-xylenol. vironment. This is in contrast to the more The length of a phenol molecule measured common situation of nonhydrogen bonding or through the oxygen-aromatic ring axis using weak hydrogen bonding molecules, in which Courtauld models is 7.7 A and its breadth is water-structuring would favor their transfer 6.3 A. The oxygen-oxygen distance in an EO to the micelle core, analogous to the formation chain arranged in the meander conformation of a hydrophobic bond. is 3.8 A (32) hence a phenol molecule H-bonded to oxygen and with its ring plane parallel to SUMMARY the EO chain axis could feasibly interfere with (1) The cloud point of aqueous cetomacrogol hydration of two to three EO units along its molecular length and possibly an additional is depressed steeply by increase in concentraone across its width, so that the 3.6 ratio value tion of phenol, cresols, or xylenols to below is not unreasonable. In the zig-zag conforma- room temperature. In the case of benzoic acid tion however, the EO chain is more extended the cloud point curve meets the solubilization curve at 44 °, which is the minimum cloud and fewer units would be blocked. With regard to the cresols and xylenols, al- point. (2) Salt depresses the cloud point and lowers though the dimensions are greater (length through oxygen-ring axis: p-methyl com- the solute concentrations required for phase pounds, ca. 8.6 A; maximum breadth, perpen- separation, due mainly to its effects on micellar dicular to oxygen-ring axis: 7.35 A for o-, m- binding. 5
0.08
'5'
Journal of Colloid and Interface Science,
Vp
V o l . 57, N o . 1, O c t o b e r 1 9 7 6
SOLUBILIZATION II
(3) The effect of a phenol on cloud point is inversely related to its hydrophobicity. (4) Concentrations needed to reduce the cloud point to 25 ° fall towards a limiting value of ca. 2.24 mole bound phenol/mole surfactant for the most lipophilic homologues, free concentrations falling to very low values. The mechanism is discussed. ACKNOWLEDGMENTS The authors are grateful to Mrs. P. Fischer and Mr. Y. Peres for their technical assistance. Some of this work formed part of a thesis submitted by E. Azaz to the Hebrew University of Jerusalem for the Ph.D. degree. REFERENCES 1. MACLAY,W. N., J. Colloid Sei. 11, 272-285 (1956). 2. SAITO,H. ANDSHINODA,K., J. Colloid Interface Sci. 24, 10-15 (1967). 3. ELWORTHY, P. H., FLORENCE, A. T., AND MACFARLANE, C. B., "Solubilization by SurfaceActive Agents and its Application in Chemistry and Biological Sciences," Chapman and Hall, London, 1968. 4. WEIDEN, M. H. J. AND NORTON, L. B., J. Colloid Sci. 8, 606-610 (1953). 5. NAKAGAWA,T. AND TORI, K., Kolloid Z. 168, 132139 (1960). 6. SHINODA,K., in "Solvent Properties of Surfactant Solutions," (Shinoda, Ed.), (a) p. 27, (b) p. 11. Marcel Dekker, New York, 1967. 7. BAL~BRA, R. R., CLUNIE, J. S., CORKILL, J. M., AND GOODMAN,J. F., Trans. Faraday Soc. 58, 1661 (1962). 8. NAKAGAWA,T., KURYAMA,K., AND INONUE, H., J. Colloid Sci. 15, 268-277 (1950). 9. ARAI, H., Y. Colloid Interface Sci. 53, 348-351 (1967). i0. SCmCK, M. J., J. Colloid Sci. 17, 801-813 (1962). 11. DOREN, A. AND GOLDFARB,J., J. Colloid Interface Sci. 32, 67-72 (1970).
27
12. NAKAGAWA,T., in "Nonionic Surfactants," p. 558. (Schick, Ed.) Marcel Dekker, New York, 1967. 13. MANXOWICH,A. M., Ind. Eng. Chem. 47, 2175-2181 (1955). 14. RIEGEL~N, S., ALLAWALA,N. A., Hg.ENOFF, M. K., ANDSTRAIT,L. A., J. Colloid Sci. 13, 208-217 (1958). 15. ATTWOOD,D., ELWORTHY,P. H., AND KAYNE, S. B., J. Pharm. Pharmacol. 23, 77S-84S (1971). 16. HADGRAFT,J. W., J. Pharm. Pharmacol. 6, 816829 (1954). 17. EVANS, W. P., J. Pharm. Pharmacol. 16, 323-331 (1964). 18. LIVINGSTON, H. K., J. Colloid Sci. 9, 365-368 (1954). 19. FRANK,H. S. ANDEVANS, M. W., J. Chem. Physics 13, 507 (1945). 20. ROBINSON,R. A. AND STOKES,R. H., "Electrolyte Solutions," 2nd ed. Butterworths, London, 1959. 21. WISHmA, A., J. Phys. Chem. 67, 2079-2082 (1963). 22. MUKERJEE, P., Advan. Colloid Interface Sei. 1, 241-275 (1967). 23. DONBROW,M., MOLYNEUX,P., ANDRHODES, C. T., J. Chem. Soc. (A), 561-565 (1967). 24. DONBROW,M. AND RHODES, C. T., J. Chem. Soe., Supplement 2, 6166-6171 (1964). 25. LEO, A., HANSCH, C., AND ELKINS, D., Chem. Rev. 71, 525-616 (1971). 26. WINsoa, P. A., "Solvent Properties of Amphiphilic Compounds," p. 135, Butterworths, London, 1954. 27. MULLEY, B. A. in "Advances in Pharmaceutical Sciences," Vol. 1, p. 145. (Bean, Beckett, and Carless, Eds.), Academic Press, New York, 1964. 28. KURIYAMA,K., Kolloid Z. 180, 55 (1962). 29. SCHOTT,H., J. Pharm. Sci. 58, 1443-1449 (1969). 30. DONBROW, M., HAMBURGER, R., AND AZAZ, E., Y. Pharm. Pharmacol. 27, 160-166 (1975). 31. KABADI,B. N. ANDHAM_MERLUND,E. R., J. Pharm. Sci. 55, 1069-1076 (1966). 32. ROSCH, M., in "Nonionic Surfactants," p. 753. (Schick, Ed.), Marcel Dekker, New York, 1967. 33. AzAz, E. AND DONBROW, M., J. Colloid Interface Sci. 56, (1976). (Part I of this article). 34. AzAz, E. AND DONBROW,M., unpublished data.
Journal of Colloid and Interface Science, Vol. 57. No. 1, October 1976