JOURNAL OF COLLOID AND INTERFACE SCI.ENCE 205, 496- 502 (1998)
`ARTICLE NO. CS985721
`
`Comparing the Surface Chemical Properties and the Effect of Salts on
`the Cloud Point of a Conventional Nonionic Surfactant, Octoxynol 9
`(Triton X-1 00), and of Its Oligomer, Tyloxapol (Triton WR-1339)
`
`Hans Schott
`
`School of Pharmacy, Temple University, Philadelphia, Pennsylvania 19140
`
`Received March 3, 1998; revised June 5, 1998
`
`The surface-chemical properties, critical micelle concentra(cid:173)
`tions (CMC), and effect of salts on the cloud points (CP) of
`octoxynol 9 (Triton X-100) and tyloxapol (Triton WR-1339)
`were compared. The latter nonionic surfactant is essentially a
`heptamer of the former. Even though the molecular weight of
`tyloxapol is 7 times larger than that of octoxynol 9, its area per
`molecule adsorbed at the air-water interface is only twice as
`large. This suggests an unusual orientat ion for molecules of
`tyloxa pol at the surface and is in keeping with a plateau that is
`less horizontal and has a somewhat higher surface tension than
`the plateaus of most nonionic surfactants. The CMC of octoxy(cid:173)
`nol 9 was 4.4 times larger than that of tyloxapol. Unexpectedly,
`the CP of dilute aqueous tyloxapol solutions was 2s•c higher
`than that of octoxynol 9 solutions. The salting-out ions Na + ,
`Cl- and so~- lowered the CP of tyloxapol 29% more than that
`of octoxynol 9. However, because the blank tyloxapol solution
`started out with a higher CP value, its CPs in the presence of
`salts were higher than those of octoxynol 9. Pb2+ and Mg2 +
`cations salted both surfactants in, raising their CP, Pb2 + more
`extensively than Mg2+. 0 1998 Academic Press
`Key Words: cloud points of octoxynol 9 and tyloxapol; critical
`micelle concentrations of octoxynol 9 and tyloxapol; octoxynol 9;
`oligomeric nonionic surfactant; salt effects on cloud points of
`octoxynol 9 and tyloxapol; surface tensions of octoxynol 9 and
`tyloxapol; Triton X-100; tyloxapol.
`
`INTRODUCTION
`
`Tyloxapol (Triton WR-1339) is a nonionic surfactant whose
`study is of practical and theoretical interest. Its practical useful(cid:173)
`ness stems from the fact that it is official in the USP employed not
`only as a detergent in preparations for cleaning contact lenses but
`also as a mucolytic agent in preparations for treating pulmonary
`diseases (I , 2). It interacts with plasma lipoproteins (3, 4), which
`rules out its use in injectable preparations.
`Tyloxapol is essentially an oligomer of octoxynol 9 (Tri(cid:173)
`ton X-1 00). Comparison with its monomer is of physico(cid:173)
`chemical importance. The effects of polymerization on the
`solution properties of monomeric surfactants have not been
`investigated beyond their dimers (5) and trimers (6),
`
`whereas tyloxapol is essentially a heptamer of octoxynol 9
`(see below).
`The purpose of the present study is to compare the surface
`activity and the critical micelle concentration (CMC) of the
`two nonionic surfactants and their interaction with electro(cid:173)
`lytes. Such interaction is conveniently investigated by
`changes in cloud point (CP). Extensive data on the effect of
`electrolytes on the CP of octoxynol 9 have been published
`(7). The CP is the lower consolute temperature of nonionic
`surfactant solutions. It is a sensitive indicator of their inter(cid:173)
`action with additives.
`The practical importance of the CP lies in the fact that
`suspensions (8), emulsions (9), and ointments and foams (I 0)
`stabilized with nonionic surfactants become unstable when
`heated in the vicinity of the CP, e.g., during manufacturing,
`steam sterilization, or some end uses. On the other hand, the
`rate of solubilization by non ionic surfactant solutions increases
`near their CP ( 11 ).
`
`EXPERIMENTAL
`
`Materials
`
`Octoxynol 9 NF is p-octylphenol ethoxylated to an average
`p value of 9.5. The octyl moiety is I, I ,3,3-tetramethylbutane;
`i.e., it is an isobutylene dimer:
`
`~CH2CH20),H
`
`Octoxynol9
`
`CgH 17
`
`The molecular weight of octoxynol 9 is ~ 625. Subsequently,
`this compound is referred to simply as octoxynol.
`Ty1oxapol USP is made by treating an excess of octy1phenol
`with fonnaldehyde in the presence of an acid catalyst, which
`causes condensation polymerization via methylene bridges in
`the ortho position. The resulting novolac oligomer is then
`ethoxylated to an average p value of 9.6 ::!:: 0. 1 (I , 2):
`
`0021-9797/98 S25.00
`Copyright <0 1998 by Academic Press
`All rights of reproduction in any form reserved.
`
`496
`
`LUPIN EX1024, Page 1
`
`

`
`COMPARING OCTOXYNOL 9 AND ITS OLIGOMER TYLOXAPOL
`
`497
`
`O(CH 2CH20)PH
`
`H
`
`CH2- -+ --r"
`
`Tyloxapol
`
`n
`
`Its molecular weight of 4500 (4) corresponds to an average n
`value of 6: Tyloxapol is a heptamer. Despite the methylene
`bridges, it has practically the same hydrophilic- lipophilic bal(cid:173)
`ance as octoxynol (see Table 1). The tyloxapol sample used,
`Aldrich Lot No. 05907 TG, had a moisture content of 0.42%
`determined by drying over P20 5 .
`Measurements with octoxynol were made with Triton X-100
`Lot No. IS682323, a gift of Union Carbide Corp., except for
`the previously published values quoted in the tables, which are
`based on other lots. All other chemicals were ACS grade. The
`water was double distilled.
`
`Swface Tension Measurements
`
`Two tyloxapol stock solutions containing 1.138 and 3.944
`giL, respectively, were equilibrated for ~ 24 b. Volumetric
`aliquots were diluted to I 00 ml in volumetric flasks. To prevent
`depletion of surfactant from the diluted solutions by adsorption
`onto the glass surfaces of the volumetric flasks and of the
`crystallizing dishes used to measure surface tensions, both
`types of glassware were prerinsed with surfactant solutions of
`the intended final concentrations. By presaturating the glass
`surfaces with the equilibrium amount of adsorbed surfactant
`corresponding to each final concentration, no surfactant was
`adsorbed onto glass from the final solutions used to measure
`surface tensions.
`
`TABLE 1
`Comparison of Some Physical Properties
`of Octoxynol 9 and Tyloxapol
`
`Property
`
`Octoxynol9
`
`Tyloxapol
`
`HLBa
`Molecular weight of monomer
`Micellar molecular weight
`-dyld In c at saturation
`adsorption (dyne/cmt
`Area per molecule in air-water interface
`1
`at saturation adsorption (A 2
`)'
`Critical micelle concentration (giL)
`Cloud point of 2.00% surfactant
`solution (0 C}
`
`13.4
`625
`86,00if
`
`13.2
`450<t
`I80,000h
`
`7.62
`
`54
`0. 17
`
`65.5
`
`3.89
`
`105
`0.0385
`
`93.8
`
`a Hydrophilic-lipophilic balance, defined as 1/5 of the weight-percent of
`ethylene oxide.
`b Reference ( 4).
`c Reference ( 13).
`d Defined by Eq. (I].
`
`50
`
`\
`
`'
`
`e u
`";; 45
`c:
`
`~ z
`0 c;;
`~40
`1-
`
`w u <[
`~ 35
`
`::;)
`(I)
`
`30
`
`- 6
`
`-4
`
`- 2
`ln(c. oiL)
`FIG. 1. Surface tension versus the natural logarithm of concentration c for
`tyloxapol at 22 ::!: I °C (empty circles) and for octoxynol 9 at 25.0 ::!: 0.2°C (full
`cin:l~:s). Tht! regions uf satumtiun at.lsurptiun and plateau surfact! ltmsiun an:
`shown as solid lines.
`
`0
`
`2
`
`This precaution was required by the low CMC value of
`tyloxapol and the even lower surfactant concentrations in
`the saturation adsorption region. Without the prerinses, the
`negative value of the slope of the linear segment of the
`surface tension versus In concentration curve in Fig.
`I
`corresponding to the saturation adsorption region would
`have been increased by > l 0%. This increase would have
`lowered the CMC by a mere ~4%. However, it would have
`lowered the area A per surfactant molecule adsorbed at
`surface saturation by > I 0% according to the Gibbs adsorp(cid:173)
`tion equation,
`
`[l]
`
`because this area is inversely proportional to dyld In c. In this
`equation, R is the gas constant, T = 2 9 5 °K, N A v is Avogadro's
`number, y is the surface tension in dyne!t:m, and c is the
`surfactant concentration in giL.
`Prior to measurement or their s urface tensions, the sur(cid:173)
`faces of the diluted solutions were cleaned by suction with
`glass capillaries, and the solutions were equilibrated for ~
`2 h at 22 :!: I oc. Surface tensions were measured by means
`of a Wilhelmy balance (Rosano surface tensiometer, VWR
`Scientific) equipped with a thin, rectangular, sand-blasted
`platinum blade. The instrument was calibrated with water
`and benzene.
`
`LUPIN EX1024, Page 2
`
`

`
`498
`
`HANS SCHOTI
`
`Cloud Point Measurements
`
`The surfactant- salt mixtures used for CP measurements
`were prepared by adding analyzed, concentrated salt solutions
`and water to 15.0% stock solutions of surfactant. All liquids
`were weighed out to the nearest milligram. The final surfactant
`concentration was 2.00% unless specified otherwise. The per(cid:173)
`centage is based on the weight of water present. The mixtures
`were aged ~ 24 h at room temperature in the dark prior to
`measuring their CP.
`CPs were measured visually while the solutions were blan(cid:173)
`keted with nitrogen, as described recently (7). The temperature
`interval between incipient and complete phase separation on
`
`heating was = I °C, as was the interval for the reverse process
`
`on cooling. The CP was taken as the temperature at which the
`immersed portion of the thermometer suddenly became invis(cid:173)
`ible on heating and fully visible on cooling. There was no
`hysteresis, and the six CP values observed on three successive
`heating and cooling cycles agreed within 0.2°C.
`
`RESULTS AND DISCUSSION
`
`Swface Tension and Critical Micelle Concentration
`
`The surface tension versus concentration data for tyloxapol
`and octoxynol are plotted in Fig. I , where the abscissa repre(cid:173)
`sents the natural logarithm of the surfactant concentration
`expressed as giL.
`The first linear segment, which extends from c = 0.004 to
`0.025 giL for tyloxapol, represents saturation adsorption. Its
`regression equation is
`
`y = 27.43 - 3.8905 In c
`
`(n = 6, r = -0.998).
`
`[2]
`
`The intermediate points at c = 0.0455 and 0.0683 giL fall in
`a transition region that may represent premicellar aggregation.
`The regression equation for the saturation adsorption region
`of octoxynol (c ~ 0.05 giL, before the shallow surface tension
`minimum) is
`
`-y = 9.59- 7.6 10 In c
`
`(n = 5, r = -0.999).
`
`[3]
`
`For tyloxapol, the regression equation for the second linear
`segment, which represents the plateau region and begins at c =
`0.075 giL, is
`
`y = 38.14 - 0.6022 ln c
`
`(n = II , r = - 0.977).
`
`[4]
`
`The regression equation for the plateau region of octoxynol
`after the shallow minimum, i.e., at c ~ 0.5 giL, is
`
`'Y = 30.44 - 0.176 In c
`
`(n = 4, r = -0.970).
`
`[5]
`
`For tyloxapol, the CMC is the concentration at which the
`
`two linear segments intersect and where Eqs. [2] and [4] are
`s imultaneous. The 22°C value is 0.0385 giL. The 25°C value
`obtained by replotting Fig. 3 of Ref. (4) is = 0.06 giL. The
`
`agreement between these two values is only fair.
`For octoxynol, the shallow surface tension minimum be(cid:173)
`tween the two linear segments requires a different approach
`( 12). Its CMC was taken as the concentration corresponding to
`the lowest surface tension because the surface tension mini(cid:173)
`mum is caused by traces of a poorly soluble, highly surface(cid:173)
`active fraction of low or zero degree of ethoxylation (13). As
`soon as octoxynol micelles begin to form, they solubilize this
`impurity, re moving it from the air-water interface and thereby
`causing the surface tension to rise. The surface tension mini(cid:173)
`mum is located at 0.16 giL. This value is in good agreement
`with the CMC of 0.18 giL determined by light scattering and
`dye solubilization ( 13).
`The more than fourfold ratio of the CMC values of
`octoxynol to tyloxapol is in keeping with the general obser(cid:173)
`vation that, as the molecular weight of a nonionic surfactant
`increases at constant hydrophilic- lipophilic balance (HLB),
`its CMC: decreases. This ohservation is illustrated hy com(cid:173)
`paring the CMC values at 25°C of two pairs of homoge(cid:173)
`neous polyo xyethylated normal primary alcohols C, EP hav(cid:173)
`in thei r hydrocarbon moiety, p
`ing n carbon a to ms
`oxyethylene units per molecule, and identical HLB values:
`0.072 M for C 6E4 {14) and (9.0 ± 1.9) X 10- 5 M for C 12E8
`(15, 16); 9.9 X 10- 3 M for C8E6 and 2.3 X 10- 6 M for
`C 16E 12 ( 17). Doubling of the surfactants' molecular weight
`decreased their CMC values 800- to 4000-fold.
`As expected, this effect is smaller for surfactants of higher
`molecular weight that are normally distributed, such as octoxy(cid:173)
`nol and tyloxapol. For instance, both C 12E 13_77 (MW = 792.9)
`and C 1 s~o (MW = 115 1.5) have HLB = 15.30. Their 25°C
`CMC values are 9 X 10- 5 M (interpolated) and 2 X 10- 5 M,
`respectively ( 17): a 45% increase in molecular weight reduced
`the CMC 4.5-fold.
`The surface properties of tyloxapol, illustrated in Fig. I,
`have the following three unusual features:
`
`(i) From Eq. [2], dy/d Inc = -3.890 5 dyne/em in the
`saturation adsorption region. According to Eq. [I ], the area per
`tyloxapol molecule in the air-water interface at saturation
`adsorption is 105 A2
`. This is merely twice the 54 A2 area of
`octoxynol calculated from Eq. [3]. The latter value agrees with
`the 55 A 2 area reported for a nonoxynol with the same degree
`of ethoxylation (p = 9.5) (18).
`(i i) The 22°C surface tension of tyloxapol at the CMC,
`40.1 dyne/em, is comparatively high. The 25°C surface
`tension of octoxynol beyond the shallow minimum, 31.5
`dyne/em, is more typical of the plateau surface tension of
`nonionie surfactants.
`(iii) The negative slope of the plateau surface tension region
`oftyloxapol is 3.4 times steeper than the more typical slope of
`octoxynol (compare Eqs. [4] and [5]). The temperature differ-
`
`LUPIN EX1024, Page 3
`
`

`
`COMPARING OCTOXYNOL 9 AND ITS OLIGOMER TYLOXAPOL
`
`499
`
`ence between 22 and 25°C is too small to account for these
`differences between tyloxapol and the typical nonionic surfac(cid:173)
`tant, octoxynol, to any significant extent.
`
`The comparatively small area per molecule of the oligomeric
`tyloxapol indicates an unusual molecular orientation at the
`air-water interface, such as U- or V -shaped instead of extended
`horizontally. The isooctyl chains would fill the inside of the U
`or V, squeezing out much of the water and attracting one
`another (hydrophobic effect), while the polyoxyethylene
`chains would be on the outside of the U or V in randomly
`coiled conformations, surrounded by water and fully hydrated.
`The proposed surface orientation also explains the other two
`unusual features in the surface properties of tyloxapol. The
`relatively high surface tension at the CMC results from a
`reduction in the interfacial area between water and the
`isooctane moieties as the molecules adsorbed at the surface
`bend to assume U or V shapes.
`The third unusual feature, namely, the comparatively
`steep negative slope beyond the CMC, results from a tight(cid:173)
`ening of the U or V shapes. As the bulk surfactant concen(cid:173)
`tration beyond the CMC is increased, the sides of the U- or
`V -shaped molecules are pushed closer together in order to
`make room for the adsorption of additional surfactant mol(cid:173)
`ecules at the air-water interface, in competition with their
`inclusion into micelles. This increases the deviation of the
`surface tension versus log concentration curve beyond the
`CMC from a horizontal plateau. The increased strain on the
`apex is partially offset by the increased hydrophobic attrac(cid:173)
`tion between opposing isooctane chains across the U or V as
`more water is squeezed out from inside.
`Similar unusual features, even more pronounced than those
`of tyloxapol, were reported for the surface properties of
`polyoxyethylene-polyoxypropylene-polyoxyethylene copoly(cid:173)
`mers of low molecular weight (poloxamers or Pluronics) (1 9).
`With molecular weights ranging from 1600 to 8000, their areas
`per molecule at saturation adsorption range from 64 to 146 A2
`.
`Their surface tensions at the inflection points on plots of
`surface tension versus log concentration are even higher
`than that of tyloxapol (50 ± 3 dyne/em compared to 40
`for tyloxapol), and the slopes of the approximately linear
`segments at higher concentrations are even much steeper
`than that of tyloxapol ( -dy/d In c = 13- 16 dyne/em com(cid:173)
`pared to 0.6 for tyloxapol).
`The following conformation was proposed for the polox(cid:173)
`amer chains adsorbed at the surface, based on the fact that
`"increasing the length of the hydrophobic polyoxypropylenc
`segment markedly decreases the area occupied by each mole(cid:173)
`cule. This suggests that the molecules are oriented in the
`surface in a coiled manner, with the polyoxypropylene segment
`out of the aqueous phase and the hydrophilic polyoxyethylene
`groups at both extremities of the molecules anchoring the
`polymer in the aqueous phase" ( 19).
`Such a conformation is compatible with a U or V shape,
`
`albeit an inverted one, where the coiled polyoxypropylene
`segment occupies the apex. Because the hydrophilic and
`hydrophobic moieties of poloxamers are more extensively
`segregated than those of the tyloxapol molecule and because
`the poloxamer chains are far more flexible and capable of
`forming random coils, one would expect their U or V shapes
`to be less distinct and more poorly defined than that of
`tyloxapol.
`The polyoxypropylene apex of the inverted U- or V(cid:173)
`shaped poloxamer molecules may be located above the
`aqueous phase. However, all of the U- or V -shaped tylox(cid:173)
`apol molecules are immersed inside the aqueous phase
`because the pendent polyoxyethylene chains are spaced
`evenly along their backbones. This and the greater flexibility
`of the poloxamer chains and the randomly coiled conforma(cid:173)
`tions of their polyoxyethylene and polyoxypropylene seg(cid:173)
`ments allow for greater compressibility of the surface layer
`at concentrations greater than the CMC, resulting in steeper
`negative slopes on the surface tension versus log concen(cid:173)
`tration plots than that of tyloxapol, which in tum is steeper
`than those of conventional polyoxyethylated nonionic sur(cid:173)
`factants.
`
`Cloud Points in Water
`
`The CPs of 0.50, 2.00, 3.50, and 5.00% tyloxapol solutions
`are 94.3, 93.8, 93.7, and 93.1 °C, respectively. The CPs of2.00
`and 4.00% octoxynol solutions are 65.5 and 65.6°C, respec(cid:173)
`tively.
`The following considerations lead to the prediction that
`tyloxapol should have a lower CP than octoxynol: The CP is
`the critical temperature of aqueous nonionic surfactant solu(cid:173)
`tions. At the 2.0% use level, both surfactants exist almost
`entirely in the form of micelles, whose molecular weights are
`in the range of polymers (see Table 1). Therefore, their solu(cid:173)
`tions should conform to the rules governing the phase equilib(cid:173)
`ria of polymer solutions (20).
`Polyoxyethylated non ionic surfactants, like polyethylene ox(cid:173)
`ides, are more water soluble at lower temperatures. Moreover,
`the micellar molecular weight oftyloxapol at room temperature
`is twice that of octoxynol. Therefore, on heating their aqueous
`solutions, the larger tyloxapol micelles should start to precip(cid:173)
`itate at a lower temperature than the smaller octoxynol mi(cid:173)
`celles. In the case of polyethylene oxides, the CP decreases
`with increasing molecular weight (21).
`However, contrary to the expected behavior, the CP of
`tyloxapol is 28°C higher than the C P of octoxynol. This
`discrepancy between the precipitation temperature of poly(cid:173)
`mers and the CP of nonionic surfactants is ascribed to the
`fact that the molecular weights of dissolved polymer mole(cid:173)
`cules are constant while the micellar molecular weights of
`nonionic surfactants increase with temperature. Apparently,
`as the temperature is increased, the micellar molecular
`weight of octoxynol increases faster than that of tyloxapol,
`
`LUPIN EX1024, Page 4
`
`

`
`500
`
`HANS SCHOTI
`
`reaching infinity (i.e., precipitating at the CP) at a lower
`temperature.
`
`TABLE 2
`Slopes b of Figs. 2 and 3 and Ionic Cloud Point Shift
`Values ~ for Octoxynol 9 and Tyloxapol
`
`Cloud Points in Salt Solutions
`
`Salting-out electrolytes lower the CP of nonionic surfac(cid:173)
`tants, shrinking the temperature range on the phase diagram
`where a surfactant forms undersaturated isotropic solutions
`(22). Salt effects are quantified by shifts in CP, ~. which
`represent the difference between the CP of a surfactant solution
`containing a salt and the CP of a blank solution of the same lot
`of surfactant at the same concentration. Since the CP of dif(cid:173)
`ferent lots of a given surfactant may differ by a degree of two,
`it is more convenient to use ~ rather than absolute CP values.
`Furthermore, the effects of a salt on two surfactants are best
`compared by its ~ values. Negative ~ values correspond to
`salting out.
`Most plots of ~ versus salt molality m are approximately
`straight lines passing through the origin:
`
`~ = hm.
`
`[o]
`
`The slopes b are calculated by the method of least squares:
`
`Salt
`
`Octoxynol 9
`
`Tyloxapol
`
`NaNO,
`NaCJ
`Na2SO.
`Mg(N03h
`Pb(NO,h
`
`Ion
`
`NO)
`Cl-
`so~-
`Na+
`Mg2+
`Pb2+
`
`- 6.511
`- 16
`- 72.6"
`6.7°
`23.1
`
`- 8.2
`- 21
`- 96.2
`5.6
`17.0c
`
`~ at W = 2.0 (0 C)
`
`Octoxynol 9
`
`0"
`- 10.5
`-25.5b
`- 6b
`4.5b
`9
`
`Tyloxapol
`od
`- 13
`-32
`- 8.1
`0.8
`8.5
`
`a Defined by Eq. [I].
`" From Refs. (23, 24). The other values are from the present work.
`c Extrapolated.
`d From Ref. (25).
`
`"'i~m
`b = "'im2 .
`
`m
`(.00
`0.25 0.50 0.75
`0
`0 .::---.,.---""T"----r-----,r---,
`
`[7] For plots that curve somewhat at higher concentrations, b is
`based on the linear portions only.
`The change in CP produced by a mixture of two salts
`is usually the algehraic sum of the changes in C:P produced
`by each salt separately. For instance, the CP of 2.00%
`tyloxapol in water, 2.0 m Mg(N03) 2 , and 2.5 m NaN03 is
`93.8, I 02.9, and 73.0°C, respectively. The C P of a 2.00%
`tyloxapol solution containing 2.0 m Mg(N03h + 2.5 m
`NaN0 3 is 82.2°C. ~ for 2.0 m Mg(N03h = 102.9 - 93.8 =
`9.1 oc and ~ for 2.5 m NaN03 = 73.0 - 93. 8 = -20.8°C.
`For the solution containing 2.0 m Mg(N03h + 2.5 m
`NaN0 3 , the calculated ~ is the algebraic sum of the indi(cid:173)
`20.8 = - 11.7°C. The
`vidual ~ values, namely, 9.1 -
`observed ~ is 82.2 - 93.8 = -ll.6°C, in excellent agree(cid:173)
`ment with the additive ~ value.
`The ~ values of the anions and cations of individual salts are
`also additive algebraically. The assignment of ~ values to
`individual ions is made at comparable values of an empirical
`concentration pararneler W called molal strength (23, 24),
`defined as
`
`W = "'imz,
`
`[8]
`
`-20
`
`p -40
`-<3
`
`-60
`
`-80
`
`o
`
`r.o 2.0 3.o 4.o 5.o
`m
`FIG. 2. Cloud point shift values .1. of sodium nitrate (circles), chloride
`(triangles), and sulfate (squares) for 2.00% tyloxapol as a function of salt
`molality 111.
`
`where z is the valence of the ions that constitute the salt.
`Thus, W = 2.0 corresponds to 1.0 m NaN0 3 and to 0.50 m
`Na2S0 4 or Mg(N03h The reference value is ~ N O) = 0,
`because the nitrate anion promotes neither salting out nor
`salting in (25).
`
`LUPIN EX1024, Page 5
`
`

`
`COMPARING OCTOXYNOL 9 AND ITS OLIGOMER TYLOXAPOL
`
`501
`
`0
`
`1.0
`
`m
`z.o
`
`3.0
`
`4.0
`
`8
`
`6
`
`(.) •
`c:i4
`
`2
`
`25
`
`20
`
`15 ~
`<i
`
`10
`
`5
`
`0
`
`1.5
`
`2.0
`
`water of hydration competes much more extensively with
`the ether groups of the polyoxyethylated surfactants for
`coordination sites of the central cation, leading to reduced
`binding (27).
`
`CONCLUSIONS
`
`From a practical viewpoint, the fact that the CMC of
`tyloxapol is 4.4 times smaller than that of octoxynol on a
`(w/w) basis is an advantage: Surfactants attain their maxi(cid:173)
`mum effectiveness in stabilizing emulsions, suspensions,
`ointments, and foams at the CMC. Only surfactant concen(cid:173)
`trations above the CMC contribute to micellar solubiliza(cid:173)
`tion. Therefore, surfactants with lower CMCs can be for(cid:173)
`mulated at lower use levels without compromising their
`effectiveness.
`Greater formula weights at constant hydrophi lic(cid:173)
`lipophilic balance lead to lower CMCs. Dimeric surfac(cid:173)
`tants have substantially lower CMCs than the correspond(cid:173)
`ing monomeric surfactants. This is one of the reasons
`for the current interest in the former (5). In the case of a
`cationic surfactant, the CMC decreased considerably
`when going from the monomer to the dimer and to the
`trimer (6). No CMC has been reported for an oligomer
`beyond the trimer until the present study, which deals with
`a heptamer.
`A potential advantage of oligomeric surfactants is that their
`films adsorbed at oil- water interfaces are probably more vis(cid:173)
`cous than the interfacial fi lms of their monomers, which should
`promote greater emulsion stability.
`Anothe r practical advantage of tyloxapol over octoxynol
`is the higher CP of the former in the absence and presence
`of salts. This is helpful in the manufacture of pharmaceu(cid:173)
`tical and cosmetic absorption- and emulsion-base oint(cid:173)
`ments, which is carried out above the melting points of
`the lipid ingredients, because disperse systems formulated
`with nonionic surfactants lose their stabil ity when heated
`above the CP.
`
`REFERENCES
`
`I. Hanson, G. R., in " Remington; The Science and Practice of Pharmacy"
`(A. R. Gennaro, Ed.), 19th ed., Vol. II, Chap. 56. Mack, Easton, PA,
`1995.
`2. Reynolds, J. E. F., Ed., "Martindale, The Extra Phannacopoeia," 31st ed.,
`p. 1347. Royal Pharmaceutical Soc., London, 1996.
`3. Cornforth, J. W., D'Arcy Han, P., Rees, R. J. W., and Stock, J. A., Nalure
`168, 150 (1951).
`4. Yamamoto, K., Byrne, R., Edelstein, C .. Shcn, B., and Scanu, A. M., J.
`Lipid Res. 25, 770 {1984).
`5. lana, R., Langmuir 11, 1208 {1996).
`6. Zan a, R., Current Opinion Colloid lnterji>ce Sci. I, 566 ( 1996).
`7. Schott, H., J. Colloid lnlelface Sci. 189, 117 ( 1997), and additional
`references Listed.
`8. Schott, H., and Royce, A. E., Colloidr Swf. 19, 399 ( 1986).
`9. Schott, H., and Royce, A. E., J. Pharm. Sci. 72, 1427 (1983).
`10. Schott, H., J. Am. Oil Chem. Soc. 65, 1658 (1988).
`
`0
`0
`
`0.5
`
`1.0
`
`m
`FIG. 3. Cloud point shift values .l of the nitrates of magnesium (circles)
`and lead (triangles) for 2.00% tyloxapol (empty symbols) and for 2.00%
`octoxynol 9 (full symbols) as a function of salt molality m.
`
`Since!::.. oftyloxapol in 0.50 m Mg(N03h = 94.6 - 93.8 =
`(2)(0) =
`0.8°C, !::.. Mg2+ = !::.. Mg(N03) 2 - 2 !::.. NO) = 0.8 -
`0.8°C at W = 2.0. Likewise,!::.. for 1.0 m NaN03 = -8.l°C,
`which equals!::.. Na+ at W = 2.0. Hence, tyloxapol is weakly
`salted in by Mg2+ and strongly salted out by Na +.
`Figure 2 shows the !::.. versus m plots for tyloxapol with
`three sodium salts. The corresponding plots for octoxynol
`have been published (7, 26). The cation and the Cl- and
`SO~- anions salt the surfactants out while the NO) anion is
`neutral.
`The six negative b and !::.. values for tyloxapol in Table 2
`are on average 1.29 ::!:: 0.04 times larger than the correspond(cid:173)
`ing negative b and !::.. values of the same ionic species for
`octoxynol. The relative standard deviation of the mean is
`only 3%, indicating very good agreement among the s ix
`ratios.
`As expected (20), tyloxapol, whose micellar molecular
`weight at room temperature is twice that of octoxynol, is salted
`out more strongly than octoxynol; i.e., its CP is lowered more
`extensively. Its negative band!::.. values are 29% larger than the
`corresponding values for octoxynol.
`The !::.. versus m curves of Mg(N03) 2 and Pb(N0 3h for the
`two surfactants are shown in Fig. 3. Some of the points for
`octoxynol were published previously (26). The two divalent
`cations Mi+ and Pb2+ salt the surfactants in through com(cid:173)
`plexation with their ether groups ( 13, 26), raising their CP
`presumably by imparting a weak positive charge to the non(cid:173)
`ionic micelles. The positive b and !::.. values of Pb2+ are larger
`than those of Mg2+ (see Table 2).
`The most likely explanation for this observation is that
`Mg2
`+ is much more strongly hydrated than Pb2
`+, and its
`
`LUPIN EX1024, Page 6
`
`

`
`502
`
`HANS SCHOTI
`
`II. Carroll, B. J., O' Rourke, B. G. C., and Ward, A. J. 1., J. Pharm. Phar-
`macal. 34, 287 (1982).
`12. Schott, H., and Han, S. K., J. Phann. Sci. 65, 975 (1976).
`13. Schott, H., J. Colloid Interface Sci. 173, 265 (1995).
`14. Schubert, K.-V., Strey, R., and Kahlweit, M., J. Colloid b11e1jace Sci. 14 1,
`21 (1991 ).
`15. Meguro, K., Takasawa, Y., Kawahashi, N., Tabata, Y., and Ueno, M., J.
`Colloid lnte1jace Sci. 83, 50 (1981).
`16. Rosen, M. J., Cohen, A. W., Dahanayake, M., and Hua, X.-Y., J. Phys.
`Chem. 86, 54 1 (1982).
`17. Becher, P., in "Nonion ic Surfactants" (M. J. Schick, Ed.), Chap. 15.
`Dekker, ew York, 1967.
`18. Hsiao, L., Dunning, H. N ., and Lorenz, P. B., J. Phys. Chem. 60, 657 (1956).
`
`., Luong, T. T., Florence, A. T., Paris, J., Vaution, C., Seiller,
`19. Prasad, K.
`M., and Puisieux, F., J. Colloid Interface Sci. 69, 225 (1979).
`20. Billmeyer, F. W., "Textbook of Polymer Science," 3rd. ed., Chap. 7D.
`Wiley, New York, 1984.
`21. Kjellander, R., and Florin, E., J. Chen1. Soc. Faraday Trans. I 77,2053
`(1981).
`22. Schott, H., and Han, S. K., J. Pharm. Sci. 65, 979 (1976).
`23. Schott, H., and Royce, A. E., J. Pharm. Sci. 73, 793 (1984).
`24. Schott, H., Royce, A. E., and Han, S. K., J. Colloid Interface Sci. 98, 196
`( 1984).
`25. Schott, H., Colloids Swf 11, 51 ( 1984).
`26. Schott, H., J. Colloid lnte1jace Sci. 43, 150 (1973).
`27. Schott, H., J. Colloid lnte1jace Sci. 192,458 (1997).
`
`LUPIN EX1024, Page 7