-
`
`288
`
`CHAPTER 19
`
`greater reduction of surface tension that occurs at lower
`concentrat ions for longer chain-length compounds. In ad(cid:173)
`dition, note the greater slopes with increasing concentration,
`indicating more adsorption (Eq 30), and the abrupt leveling
`of surface tension at higher concentrations. This latter be(cid:173)
`havior reflects the self-association of surface-act ive agent to
`form micelles which exhibit no further tendency to reduce
`surface tension. The topic of micelles will be discussed later
`on page 268.
`If one plot.a the values of surface concentration, I', vs
`concentration, c, for substances adsorbing to the vapor-liq(cid:173)
`uid and liquid-liquid interfaces, using data such as those
`given in Fig 19-13, one generally obtains an adsorption iso(cid:173)
`therm shaped like those in Fig 19-9 for vapor adsorption.
`Indeed, it can be shown that the Langmuir equation (Eq 26)
`can be fitted to such data when written in the form
`I'max k'c
`r= .....;.;~-
`1 + k'c
`where I' mu is the maximum surface concentra tion attained
`with increasing concentration and h' is related to k in Eq 26.
`Combining Eqs 29 and 31 leads to a widely used relationship
`between surface tension change Il (see Eq 28) and solute
`concentration, c, known as the Syszkowski equation:
`Il = I'max RT In (1 + k'c)
`
`(32)
`
`(31)
`
`Mixed Films
`It would seem reasonable to expect that the properties of a
`surface film could be varied greatly if a mixture of surface(cid:173)
`active agents were in the film . As an example, consider that
`a mixture of short- and long-chain fatty acids would be
`expected to show a degree of "condensation" varying from
`the "gaseous" state, when the short-chain substance is used
`in high amount, to a highly condensed state when the longer
`chain substance predominates. Thus, each component in
`such a case would operate independently by bringing a pro(cid:173)
`portional amount of film behavior to the system.
`More often, the ingredients of a surface film do not behave
`independently, but, rather, interact to produce a new surface
`film . An obvious example would be the combination of
`organic amines and acids which are oppositely charged and
`would be expected to interact strongly.
`In addition to such polar-group interactions, chain-chain
`interaction will strongly favor mixed condensed films. An
`important example of such a case occurs when a long-chain
`alcohol is introduced along with an ionized long-chain sub(cid:173)
`stance. Together the molecules form a highly condensed
`film despite the presence of a high number of like charges.
`Presumably this occurs as seen in Fig 19-14, by arranging the
`molecules so that ionic groups alternate with alcohol groups;
`however, if chain-chain interactions are not strong, the ionic
`species often will be displaced by the more nonpolar union(cid:173)
`ized species a nd "desorb" into the bulk solution.
`On the other hand, sometimes the more soluble surface(cid:173)
`act ive agent produces surface pressures in excess of the col(cid:173)
`lapse pressure of the insoluble film and displaces it from the
`surface. This is an important concept because it is the
`underlying principle behi nd cell lysis by surface-active
`agents and some drugs, and behind the important process of
`detergency.
`
`Adsorption on Solid Surf aces From S olution
`Adsorption to solid surfaces from solution may occur if
`dissolved molecules and the solid surface have chem
`groups capable of interacting. Nonspecific adsorption .
`will occur if the solute is surface active and if the surface 1
`of the solid is high. This latter case would be the sarn.
`occurs at the vapor-liquid and liquid-liquid interfaces.
`with adsorption to liquid interfaces, adsorption to solid:
`faces from solution generally leads to a monomolecular
`er, often described by the Langmuir equa tion or by
`empirical, yet related, Freundlich equation
`
`x/M= ken
`where x is the grams of solute adsorbed by M grams of s
`in equilibrium with a solute concentration of c. The terr
`and n are empirical constants. However, as Giles8
`pointed out, the variety of combinations of solutes and
`ids, and, hence the variety of possible mechanisms of ads,
`tion, can lead to a number of more complex isotherms.
`particular, adsorption of surfactants and polymers, of g
`importance in a number of pharmaceutical systems, is
`not well understood on a fundamental level, and ma·
`·
`some situations even be multilayered.
`Adsorption from solution may be measured by separa
`solid and solution and either estimating the amount of
`sorbate adhering to the solid or the loss in concentratio
`adsorbate from solution.
`In view of the possibility of solvent adsorption, the la
`approach really only gives an apparent adsorption.
`example, if solvent adsorption is great enough, it is poss
`to end up with an increased concentration of solute a
`contact with the solid; here, the term negative adsorptic
`used.
`Solvent not only influences adsorption by competing
`the surface but, as discussed in connecti.on with adsorp
`at liquid surfaces, the solvent will determine the esca1
`tendency of a solute; eg, the more pola r the molecule, the
`the adsorption that occurs from water. This is seen in
`19-15, where adsorption of various fatty acids from w.
`onto charcoal increases with increasing alkyl chain lengt
`nonpolarity. It is difficult to predict these effects bul
`general, the more chemically unlike the solute and soh
`and the more alike the solid surface groups and solute,
`
`u
`E
`
`0 .. c:I .. 1
`
`4
`
`3
`
`:
`0
`~ 2
`i
`i
`"
`
`Fig 19-14. A mixed monomolecular film. ®: a long-chain ion; O:
`a long-chain nonionic compound.
`
`0 '-----...&... _ _ _ ......_ _ _ _ ......
`0
`2
`3
`Coneent,atlon, Molu Pff Lit.-
`Fig 19-15. The relation between adsorption and molecular wei,
`fatty acids. 9
`
`FRESENIUS EXHIBIT 1013
`Page 65 of 408
`
`

`

`,he
`Ca]
`lao
`:ea
`as
`As
`ur.
`1;,.
`;he
`
`33)
`
`•lid
`.a k
`'.las
`IOI-
`rp.
`In
`eat
`tiU
`in
`
`ing
`ad-
`I Of
`
`.ter
`ror
`ble
`·ter
`n is
`
`for
`ion
`ing
`es&
`Fig
`ter
`1or
`, in
`ent
`the
`
`.,
`
`?
`'.;
`
`Fig 19-16. The adsorption o l a cationic surlactant, LW, onto a
`oegalfvely charged silica or glass surlace, exposing a hydrophObic
`surface as the solid is exposed to a ir. 10
`
`greater the extent of adsorption. Another factor which
`must be kept in mind is that charged ~olid _surfaces, such as
`polyelectrolyte~. will strongly adsorb opp_o~1te!y c~arged s~l(cid:173)
`utes. This is similar t.o the strong spec1f1c binding seen m
`gas chemisorption and it is characterized by significant
`monolayer adsorption at very low concentrations of solute.
`See Fig 19·16 for an example of such adsorption.
`
`Surface-Active Agents
`
`Throughout the discussion so far, examples of sur face (cid:173)
`active agents (surfactants) have been restricted primarily to
`fatty acids and their salts. It has been shown that both a
`hydrophobic portion (alkyl chain) and a hydrophilic portion
`(carboxyl and carboxylate groups) are required for their
`surface activity, the relative degree of polarity determining
`the tendency to accumulate at interfaces. It now becomes
`important to look at some of the specific types of surfactants
`available and to see what structural features are required for
`different pharmaceutical applications.
`The classification of surfactants is quite arbitrary, but one
`~ased on chemical structure appears best as a means of
`~traducing the topic. It is generally convenient to catego(cid:173)
`nze surfactants according to their polar portions since t he
`;onpol~ portion is usually made up of alkyl or aryl groups.
`_h! maJor polar groups found in most surfactants may be
`f v!ded as follows: anionic, cationic, amphoteric and non-
`
`0.~c. As we shall see, t he last group is the largest and most
`WJ ely used for pharmaceutical systems, so that it will be
`emphasized in the discussion that follows.
`
`Types
`facAnionic Agents-The most commonly used anionic sur(cid:173)
`sulftan~ are those containing carboxylate, sulfonate, and
`ate •ons. Those containing carboxylate ions are known
`48 5
`na~a~sr8nd are generally prepared by the saponification of
`att}'. acid glycerides in alkaline solution. The most
`Corn r
`um mon catt?ns associated with soaps are sodium, potassi(cid:173)
`len~:~lll.on,um, and triethanolamine, while the chain
`Th O the fatty acids ranges from 12 to 18.
`len~ d?ree of water solubility is greatly influenced by the
`For ex. 0 the alkyl chain and the presence of double bonds.
`r0om ~In.pie, sodium stearate is quite insoluble in water at
`conditi mp~rature, whereas sodium oleate under the same
`ans 19 quite water soluble.
`
`... . .
`'
`
`DISPERSE SYSTEMS
`
`267
`
`Table VII-Effect of Aerosol OT Con<:entratlon on the
`Sur1ace Tension of Water and the Contact Angle of Water
`with Magnesium Stearate
`
`ConcentratJOn,
`mX 106
`
`1.0
`3.0
`5.0
`8.0
`10.0
`12.0
`15.0
`20.0
`25.0
`
`'Y ., ..
`
`60.l
`49.8
`45.1
`40.6
`38.6
`37.9
`35.0
`32.4
`29.5
`
`8
`
`120°
`113°
`104°
`89°
`so·
`71.
`63°
`54°
`50•
`
`Multivalent ions, such as calcium and magnesium, pro(cid:173)
`duce marked water insolubility, even at lower alkyl chain
`lengths; thus, soaps are not useful in hard water which is
`high in content of these ions. Soaps, being salts of weak
`acids, are subject also to hydrolysis and the formation of free
`acid plus hydroxide ion, particularly when in more concen(cid:173)
`trated solution.
`To offset some of the disadvantages of soaps, a number of
`long-alkyl-chain sulfonates, as well as alkyl aryl sulfonates
`such as sodium dodecylbenzene sulfonate, may be used; the
`sulfonate ion is less subject to hydrolysis and precipitation in
`the presence of mult ivalent ions. A popular group of sulfo(cid:173)
`nates, widely used in pharmaceutical systems, are the dial(cid:173)
`kyl sodium sulfosuccinates, particularly sodium bis-(2-
`ethylhexyl)sulfosuccinate, best known as Aerosol OT or do(cid:173)
`cusate sodium. This compound is unique in that it is both
`oil and water soluble and hence forms micelles in both
`phases.
`It reduces SUJ'face and interfacial tension to low
`values and acts as an excellent wetting agent in many types
`of solid dosage forms (see Table VII) .
`A number of alkyl sulfates are available as surfactants, but
`by far the most popular member of this group is sodium
`lauryl sulfate, which is widely used as an emulsifier and
`solubili2er in pharmaceutical systems. Unlike the sulfo(cid:173)
`nates, sulfates are susceptib le to hydrolysis which leads to
`the formation of the long-chain alcohol, so that pH control is
`most important for sulfate solutions.
`Cationic Agents- A number of long-chain cations, such
`as amine salts and quaternary ammonium salts, are often
`used as surface-active agents when dissolved in water; how(cid:173)
`ever, their use in pharmaceutical preparations is limited to
`that of antimicrobial preservation rather than as surfac(cid:173)
`tants. T his arises because the cations adsorb so readily at
`cell membrane structures in a nonspecific manner, leading
`to cell lysis (eg, hemolysis), as do anionics to a lesser extent.
`It is in this way that they act to destroy bacteria and fungi.
`Since anionic a.nd nonionic agents are not as effective as
`preservatives, one must conclude that the positive charge of
`these compounds is important; however. the extent of sur(cid:173)
`face activity has been shown to determine the amount of
`material needed for a given amount of preservat ion. Qua(cid:173)
`ternary ammonium salts are preferable to free amine salts
`since they are not !iubject to effect by pH in any way; howev(cid:173)
`er, the presence of organic anions such as dyes and natural
`polyelectrolytes is an important source of incompatibility
`and such a combination should be avoided.
`Amphoteric Agents- The major group of molecules fall(cid:173)
`ing into th is category are t hose containing carboxylate or
`phosphate groups as the anion and amino or quaternary
`ammonium groups as the cation. The former group is repre(cid:173)
`sented by various polypeptides, proteins, and the alkyl beta(cid:173)
`ines, while the latter group consist of natural phospholipids
`such as the Lecithins and cephalins. In general, long-chain
`amphoterics which exist in solution in 2witterionic fo rm are
`
`FRESENIUS EXHIBIT 1013
`Page 66 of 408
`
`

`

`268
`
`CHAPTER 19
`
`more surface-active than ionic surfactants having the same
`hydrophobic group since in effect the oppositely charged
`ions are neutralized. However, when compared to nonion(cid:173)
`ics, they appear somewhere between ionic and nonionic.
`Nonionic Agents-The major class of compounds used
`in pharmaceutical systems are the nonionic surfactants since
`their advantages with respect to compatibility, stability, and
`potential toxicity are quite significant. It is convenient to
`divide these compounds into those that are relatively water
`insoluble and those that are quite water soluble.
`The major type of compounds making up this first group
`are the long-chain fatty acids and their water-insoluble de(cid:173)
`rivatives. These include (1) fatty alcohols such as lauryl,
`cetyl (16 carbons) and stearyl alcohols; (2) glyceryl esters
`such as the naturally occurring mono-, di- and triglycerides;
`and (3) fatty acid esters of fatty alcohols and other alcohols
`such as propylene glycol, polyethylene glycol, sorbitan, su(cid:173)
`crose and cholesterol. Included also in this general class of
`nonionic water-insoluble compounds are the free steroidal
`alcohols such as cholesterol.
`To increase the water solubility of these compounds and
`to form the second group of nonionic agents, polyoxyethy(cid:173)
`lene groups are added through an ether linkage with one of
`their alcohol groups. The list of derivatives available is
`much too long to cover completely, but a few general catego(cid:173)
`ries will be given.
`The most widely used compounds are the polyoxyethylene
`sorbitan fatty acid esters which are found in both internal
`and external pharmaceutical formulations. Closely related
`compounds include polyoxyethylene glyceryl, and steroidal
`esters, as weU as the comparable polyoxypropylene esters.
`It is also possible to have a direct ether linkage with the
`hydrophobic group as with a polyoxyethylene-stearyl ether
`or a polyoxyethylene-alkyl phenol. These ethers offer ad(cid:173)
`vantages since, unlike the esters, they are quite resistant to
`acidic or alkaline hydrolysis.
`Besides the classification of surfactants according to their
`polar portion, it is useful to have a method that categorizes
`them in a manner that reflects their interfacial activity and
`their ability to function as wetting agents, emulsifiers, solu(cid:173)
`bilizers, etc. Since variation in the relative polarity or non(cid:173)
`polarity of a surfactant significantly influences its interfacial
`behavior, some measure of polarity or nonpolarity should be
`useful as a means of classification.
`One such approach assigns a hydrophile- lipophile balance
`number (HLB) for each surfactant and, although developed
`by a commercial supplier of one group of surfactants, the
`method has received wide-spread application. The HLB
`value, as originally conceived for nonionic surfactants, is
`merely the percentage weight of the hydrophilic group divid(cid:173)
`ed by five in order to reduce the range of values. On a molar
`basis, therefore, a 100% hydrophilic molecule (polyethylene
`glycol) would have a value of 20.
`Thus, an increase in polyoxyethylene chain length in(cid:173)
`creases polarity and, hence, the HLB value; at constant polar
`chain length, an increase in alkyl chain length or number of
`fatty acid groups decreases polarity and the HLB value.
`One immediate advantage of this system is that to a first
`approximation one can compare any chemical type of surfac(cid:173)
`tant to another type when both polar and nonpolar groups
`are different.
`HLB values for non ionics are calculable on the basis of the
`proportion of polyoxyethylene chain present; however, in
`order to determine values for other types of surfactants it is
`necessary to compare physical chemical properties reflecting
`polarity with those surfactants having known HLB values.
`Relationships between HLB and phenomena such as wa(cid:173)
`ter solubility, interfacial tension, and dielectric constant
`have been used in this regard. Those surfactants exhibiting
`values greater than 20 (eg, sodium lauryl sulfate) demon-
`
`strate hydrophilic behavior in excess of the polyoxyethylene
`groups alone. Table XIX, page 304, presents HLB values
`for a variety of surface-active agents.
`
`Surfactant Properties In Solution and Mlcelle
`Formation
`As seen in Fig 19-13, increasing the concentrat ion of sur(cid:173)
`face-active agents in aqueous solution causes a decrease in
`the surface tension of the solution until a certain concentra(cid:173)
`t ion where it then becomes essentially constant with increas(cid:173)
`ing concentration. That this change is associated with
`changes also taking place in the bulk solution rather than
`just at the surface can be seen in Fig 19-17, which shows the
`same abrupt change in bulk solution properties such as solu(cid:173)
`bility, equivalent conductance and osmotic pressure as with
`surface properties. The most reasonable explanation for
`these effects is that the solute molecules self-associate to
`form soluble aggregates which exhibit markedly different
`properties from the monomers in solution. Such aggregates
`(Fig 19-18A) appear to exhibit no tendency to adsorb to the
`surface s ince the surface and interfacial tension above this
`solute concentration do not change to any significant extent.
`Such aggregates, known as micelles, form over such a very
`narrow range of concentrations that one can speak of a criti(cid:173)
`cal micellization concentration (cmc). These micelles form
`for essentially the same reasons that cause molecules to be
`adsorbed; the lack of affinity of the hydrophobic chains for
`water molecules and the tendency for strong hydrophobic
`chain-chain interactions when the chains are oriented close(cid:173)
`ly together in the micelle, coupled with the gain in entropy
`due to the loss of the ice-like structure of water when the
`chains are separated from water, lead to a favorable free
`energy change for micellization. The longer the hydrophobic
`chain or the less the polarity of the polar group, the greater
`the tendency for monomers to "escape" from the water to
`form micelles and, hence the lower the cmc (see Fig 19-13).
`In dilute solution (still above the cmcl the micelles can be
`considered to be approximately spherical in shape (Fig 19-
`18A and Bl, while at higher concentrations they become
`
`C
`
`E
`
`A
`
`>-
`t: .,
`C.
`0
`ci:
`0
`C
`~
`c
`0 .,
`:IE
`
`+---~-=----8
`D
`
`anc
`Surfactant coocentrabon
`Fig 19- 17. Effect of surfactant concentration and micelle formation
`on various properties of the aqueous solution of an ionic surfactant
`A: Surface tension; B:
`interfacial tension; C: osmotic presst.Jfe; O:
`equivalent conductivity; E: solubility of compound with very low
`solubility in pure water 11
`
`FRESENIUS EXHIBIT 1013
`Page 67 of 408
`
`

`

`►
`
`DISPERSE SYSTEMS
`
`269
`
`-~ V. V.
`1/\,
`~v.
`V.y,,
`v. v.
`..,.,v.. V.
`v.""' y,,,,
`V.
`
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`
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`
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`
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`
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`
`y.,,
`
`v. ""'w v. v. ""
`v.."" ""v..
`v,, vi. Yw
`..,.v..
`V.
`V.·
`""
`
`V.
`
`V.
`
`w
`1/\,
`
`V.
`
`V.
`
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`
`""' y.,,
`w
`
`w
`
`y,.
`
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`
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`
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`w
`-
`
`VI,
`
`V.
`
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`
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`
`VI,
`
`1/\,
`
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`VI, V. w""
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`y,,,, V. ""
`y,,,,
`V. w
`V.
`""
`
`w
`V.
`
`V.
`
`V.
`
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`w w
`
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`1/\, w
`.,..
`
`V.
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`v,,,,
`
`,,.
`
`VI,
`
`©
`v,,,,..,,,,,
`v..,.,. w
`
`"" <ll""<ll v,,
`v....,.,
`VI,
`" " 'w " ' -
`V.
`Vv (l) V.
`w
`V.
`
`v,,
`v,,
`
`v,,
`
`1/\,
`
`""
`
`""
`
`A
`
`1/\, w
`
`V.
`
`w..,.
`v.,
`
`y,,,, "-
`
`B
`
`~
`Surface,.tive anion
`Counttfion
`Wtttr mo4ecule
`Oil molecule
`Fig 19-18. Oitferenl types of micelles. A: Spherical micelle of an anionic surfactant; B: spherical mlcelle of a nonionic surfactant; C:
`cylindl'icat mlcelle of an ionic surfactant; D: lamellar inicelle of an ',onlc slM'factant; E: reverse mlcelle of an anionic surfactant In oil. 11
`
`more asymmetric and eventually assume cylindrical (Fig 19-
`18C) or lameUar (Fig 19-18D) structures. It is important to
`recognize that equilibrium, and hence reversibility, exists
`~twe~n the monomers and t he various types of micelles.
`he sizes of such micelles depend on the number of mono(cid:173)
`!11e~s .Per micelle and the size and molecular shape of the
`llld1v1dual monomers. In Table VUI are given the cmc and
`fumLer of monomers per micelle for different types of sur(cid:173)
`tctants. Note for the nonionic surfactants that the longer
`t e f:>Olyoxyethylene chain, and hence the more polar and
`bulkier the molecule, the higher the cmc, ie the less the
`terdency for micelle formation. It is also possible for oil(cid:173)
`~ uble surfactants to show a tendency to self-associate into
`;~ers~ micelles in nonpolar solvents, as depicted in Fig 19-
`1
`' wtth their polar groups all oriented away from the
`:lvent. In general these micelles tended to be smaller and
`. aggregate over a wider range of concentrations than seen
`tn water, and therefore, to exhibit no well-defined cmc.
`
`Micellar Solubillzatlon
`
`As seen in Fig 19-18, the interior of surfactant micelles
`formed in aqueous media consists of hydrocarbon " tails" in
`liquid-like disorder. The micelles, therefore, resemble min(cid:173)
`iscule pools of liquid hydrocarbon surrounded by shells of
`polar "head groups." Compounds which are poorly soluble
`in water but soluble in hydrocarbon solvents, can be dis(cid:173)
`solved inside these micelles, ie, t hey are brought homoge(cid:173)
`neously into an overall aqueous medium.
`Being hydrophobic and oleopbilic, the solubilized mole(cid:173)
`cules are located primarily in the hydrocarbon core of the
`micelles (see Fig 19-19A). Even water-insoluble drugs usu(cid:173)
`ally contain polar functional groups such as hydroxyl,
`carbonyl, ether, amino, amide, and cyano. Upon solubiliza(cid:173)
`tion, these hydrophilic groups locate on the periphery of the
`micelle among the polar headgroups of the surfactant in
`order to become hydrated (see Fig 19-19B). For instance,
`
`FRESENIUS EXHIBIT 1013
`Page 68 of 408
`
`

`

`270
`
`CHAPTER 19
`
`Table VIII-Crltleal MiceRe ConcentraHons and Mlc:ellar Aggregation Numbers ot Various Surfactants In Water at Room
`Temperature
`
`Structure
`
`Name
`
`CMC,mM/L
`
`n-C11H23COOK
`n-CsHriS03Na
`n-C10H21S03Na
`n-C12H2r,S03Na
`n-C12H:isOSO;iNa
`n-C12H:isOS03Na
`
`n-C10H21 N(CH.-ibBr
`n•C12H:i5N(CH3}38r
`n-CuH29N(CH3)JBr
`n-C1,H29N(CH3)aCI
`n-C,2H:isNHsCI
`n-C12H,sO(CH2CH20laH
`n-C12H250(CH2CH20)8Hb
`n·C12H:is(CH2CH20l12H
`n-C12H~~O(CH2CH20l12Hb
`t-Csff1;·CeH.·O(CH,CH20 l, 7H
`
`Potassium laurate
`Sodium octant sulfonate
`Sodium decane sulfonate
`Sodium dodecane sulfonate
`Sodium lauryl sulfate
`Sodium Laury! sulfate•
`Sodium di-2-etbylhexyl sulfosuccinate
`Decyltrimethylammonium bromide
`Dodecyltrimethylammonium bromide
`Tetradecyltrimetbylammonium bromide
`Tetradecyltrimethylammonium chloride
`Dodecylammonium chloride
`Octaoxyethylene glycol monododecyl ether
`
`Dodecaoxyethylene glycol monododecyl ether
`
`Decaoxyethylene glycol mono-p,t-octylpbenyl ether (octoxynol 9)
`
`24
`150
`40
`9
`8
`l
`5
`63
`14
`3
`3
`13
`0.13
`0.10
`0.14
`0.091
`0.27
`
`• Interpolated for p hysiolog1c saline, 0 154 M NaCl.
`b At&s• instead or20•.
`
`Surtactant
`moIec~es1
`m,celle
`
`50
`28
`40
`54
`62
`96
`48
`36
`50
`75
`64
`55
`132
`301
`78
`116
`100
`
`C
`
`SURFACE ACTJVE AGENT
`
`-
`
`-
`
`POLYOXYETHYLENE CHAIN
`
`HYDROCARBON CHAIN
`
`=
`
`o=:,
`
`SURFACE
`ACTIVE
`AGENT
`Ionic surfactant (solublllzed molecule has no hydrophilic groups); B:
`Fig 19-19. The locations of solubilizates In spherical micelles. A:
`Ionic surfactant (solublllzed molecule has a hydrophilic grOilp); C: nonionic surfactant (polar solubilizate) 12
`
`SOLUBILI ZATE
`
`I
`SOLUBILIZATE
`
`when cholesterol or dodecanol is solubilized by sodium lau(cid:173)
`ryl sulfate, their hydroxyl groups penetrate between sulfate
`ions and are even bound to them by hydrogen bonds, while
`their hydrocarbon portions are immersed among the dodecyl
`tails of the surfactant which make up the core of the micelle.
`Micelles of polyoxyethylated nonionic surfactants consist
`of an outer shell of hydrated polyethylene glycol moieties
`and a core of hydrocarbon moieties. Compounds like phe(cid:173)
`nol, cresol, benzoic acid, salicylic acid, and esters of p(cid:173)
`hydroxy and p -aminobenzoic acids have some solubility in
`water and in oils but considerable solubility in liquids of
`intermediate polarity like ethanol, propylene glycol or aque(cid:173)
`ous solutions of polyethylene glycols. When solubilized by
`nonionic micelles, they are located in the hydrated outer
`polyethylene glycol shell as shown in Fig 19-19C. Since
`these compounds have hydroxyl or amino groups, they fre (cid:173)
`quently form complexes with the ether oxygens of the sur(cid:173)
`factant by hydrogen bonding.
`Solubilization is generally nonspecific: any drug which is
`appreciably soluble in oils can be solubilized. Each has a
`solubilization limit, comparable to a limit of solubility,
`which depends on temperature and on the nature and con(cid:173)
`centration of the surfactant. Hartley distinguishes two cat-
`
`egories of solubilizates. The first consists of comparatively
`large, asymmetrical and rigid molecules forming crystalline
`solids, such as steroids and dyes. These do not blend in with
`the normal paraffin tails which make up the micellar core;
`because of dissimilarity in structure, they remain distinct as
`solute molecules. They are sparingly solubilized by surfac(cid:173)
`tant solutions, a few molecules/micelle at saturation (see
`Table IX). The number of carbon atoms in the micellar
`hydrocarbon core required to solubilize a molecule of steroid
`or dye at saturation is of the same order of magnitude as the
`number of carbon atoms of bulk liquid dodecane or hexade(cid:173)
`cane per molecule of steroid or dye in their saturated solu(cid:173)
`tions in these liquids.
`Since solubilization depends on the presence of micelles, it
`does not take place below the cmc. It can, therefore, be used
`to determine the cmc, particularly when the solubilizate is a
`dye or another compound easy to assay. Plotting the maxi·
`mum amount of a water-insoluble dye solubilized by aque·
`ous surfactant, or the absorbance of its saturated solutions,
`versus the surfactant concentration produces a straight line
`which intersects the surfactant concentration axis at t he
`cmc. Above the cmc, the amount of solubilized dye is direct·
`ly proportional to the num her of micelles and, therefo re,
`
`FRESENIUS EXHIBIT 1013
`Page 69 of 408
`
`

`

`Table lX-Mlcellar SoklbUlzatlon Capacities Of Different
`Surfactants tor Estrone 13
`
`Moles
`_,actant/
`mole
`Concentration Temp, solut>ilized
`range, molarity
`estrone
`°C
`
`Su,lactant
`
`$odium Iaurate
`sodium oleate
`Sodium Iauryl sulfate
`$odium cholate
`.
`Sodium deo1ycholate
`Diamyl sodium sulfosucc~nate
`Dioctyl sodium sulfosuccUla~
`Tetradecyltrimethylammomum
`bromide
`Hexadecylpyridinium chloride
`Polysorbate 20
`Polysorbate 60
`
`0.025-0.023
`0. 002-0.35
`0.004-0.15
`0.09-0.23
`0.007-0.36
`0.08-0.4
`0.002-0.05
`
`0.005-0.08
`0.001-0.1
`0.002-0.15
`0.0008--0.11
`
`40
`40
`40
`20
`20
`40
`40
`
`20
`20
`20
`20
`
`91
`53
`71
`238
`476
`833
`196
`
`45
`32
`161
`83
`
`proportional to the overall surfactant concentration. Below
`the cmc, no solubilization takes place. This is represented
`by Curve E of Fig 19-17.
`The second category of compounds to be solubilized are
`often liquid at room temperature and consist of relatively
`small, symmetrical, and/or flexible molecules such as many
`constituents of essential oils. These molecules mix and
`blend in freely with the hydrocarbon portions of the surfac(cid:173)
`tants in the core of the micelles, so as to become indistin(cid:173)
`guishable from them. Such compounds are extensively sol(cid:173)
`ubilized and in the process usually swell the micelles:
`they
`augment the volume of the hydrocarbon core and increase
`the number of surfactant molecules per m icelle. Their solu(cid:173)
`bilization frequently lowers the cmc.
`
`Microemulsions 14- 16
`
`Microemulsions are liquid dispersions of water and oil
`that are made homogeneous, transparent, and stable by the
`addition of relatively large amounts of a surfactant and a
`cosurfactant. Oil is defined as a liquid of low polarity and
`low miscibility with water, eg, toluene, cyclohexane, mineral
`or vegetable oils.
`Microemulsions are intermediate in properties between
`micelles containing solubilized oils and emulsions. While
`emulsions are lyophobic and unstable, microemulsions are
`on the borderline between lyophobic and lyophilic colloids.
`True microemulsions are thermodynamically stable.17
`Therefore, they are formed spontaneously when oil, water,
`surfactants, and cosurfactants are mixed together. The un(cid:173)
`stable emulsions require input of considerable mechanical
`energy for their preparation, which may be supplied by col(cid:173)
`loid mills, homogenizers or ultrasonic generators.
`Both emulsions and microemulsions may contain high
`volume fractions of the internal phase. For instance, some
`O/W systems contain 75% (v/v) of oil dispersed in 25% water,
`although lower internal phase volume fractions are more
`common.
`At low surfactant concentrations, viz, low multiples of the
`cWmc, micelles are spheres (Fig 19-lBA, Band E) or ellipsoids.
`hen an oil is solubi1ized by micelles in water, it blends into
`the micellar core formed by the hydrocarbon tails of the
`surfactant molecules (Fig 19-19) and swells the micelles.
`Spherical or ellipsoidal micelles are nearly monodisperse,
`an~ their mean diameters are in the range of 25 to 60 A.
`~•croemulsion droplets also have a narrow droplet size dis(cid:173)
`t1nbutAion with a mean diameter range of approximately 60 to
`. Since the droplet diameters are less than ¼ of the
`000
`wavelength of light (4200 A for violet and 6600 A for red
`
`DISPERSE SYSTEMS
`
`271
`
`light), microemuJsions scatter little light and are, therefore,
`transparent or at least translucent.
`Emulsions have very broad droplet size distributions.
`Only the smallest droplets, with diameters of about 1000 to
`2000 A, are below the resolving power of the light micro(cid:173)
`scope. The upper size limit is 25 or 50 µm (250,000 or
`500,000 A). Because emulsion droplets are comparable in
`size, or larger than the wavelength of visible light, they
`scatter it more or less strongly depending on the difference
`in refractive index between oil and water. Thus, most emul(cid:173)
`sions are opaque.
`The three disperse systems-micellar solutions, microe(cid:173)
`mulsions, and emulsions-can be of the O/W (oil-in-water)
`or W /0 type. Aqueous micellar surfactant solutions can
`solubilize oils and lipid-soluble drugs in the core formed by
`their hydrocarbon chains. Likewise, oil-soluble surfactants
`like sorbitan monooleate and docusate sodium form "reverse
`micelles" in oils (Fig 19-18E) capable of solubilizing water in
`the polar center. The solubilized oil in the former micelles
`and the solubilized water in the latter may in turn enhance
`the micellar solubilization of oil-soluble and water-soluble
`drugs, respectively.
`Oil-soluble drugs have been incorporated into O/W emul(cid:173)
`sions by dissolving them in the oil phase before emulsifica(cid:173)
`tion.18 By the same token, it may be possible to dissolve
`oil-soluble drugs in a vegetable oil and make an oral or
`parenteral O/W microemulsion. The advantage of such mi(cid:173)
`croemulsion systems over conventional emulsions is their
`smaller droplet size and superior shelf stability. Aqueous
`micellar solutions19 and O/W microemulsions20 have both
`been used as aqueous reaction media for oil-soluble com(cid:173)
`pounds.
`Emulsions and micellar solutions of oils solubilized in
`aqueous surfactant solutions consist of three components,
`oil, water and surfactant. Microemulsions generally require
`a fourth component, called cosurfactant. Commonly used
`cosurfactants are linear alcohols of medium chain length,
`which are sparingly miscible with water. Since the cosurfac(cid:173)
`tants as well as the surfactants are surface-active, they pro(cid:173)
`mote the generation of extensive interfaces th.rough the
`spontaneous dispersion of oil in water, or vice-versa, result(cid:173)
`ing in the formation of microemulsions. The large interfa(cid:173)
`cial area