Fluid and semisolid emulsions and oil-free dis- persions structured by surfactant mixtures are widely used in pharmacy and cosmetics for their therapeutic properties and as vehicles to deliver drugs and cosmetic agents to the skin. Mobile dispersions intended for topical application are generally described as lotions or liniments and semisolid systems as creams. Although creams are usually emulsions of the oil-in-water type (aqueous creams), water-in-oil emulsions (oily creams) and other bases that have a semisolid, matrix-like appearance and are soft enough to be rubbed into the skin are also included in this category.
In the past, such formulations were often consid- ered simply as an elegant f ramework for carrying
the drug or cosmetic agent to the skin. However, it is now well established that the colloidal proper- ties of such vehicles can influence the bioavailabil- ity of the drug or cosmetic agent in a number of ways [1 3]. For example, the drug or cosmetic agent may interact with the vehicle (drug vehicle interactions) to influence its solubility in the vehi- cle, its diffusion through the vehicle and its parti- tioning from the vehicle on to the skin. The appearance and smoothness of skin as well as its permeability to topically applied drugs is directly related to the degree of hydration of the stratum corneum. This may be influenced by the vehicle alone through its ability to reduce evaporation by forming an occlusive layer when applied as a thin film. Components of the vehicle may interact with the lipid layers of the stratum corneum
(vehicle-skin interactions) to make them more permeable to drugs [4]. These individual drug-veh- icle and vehicle-skin interactions combine to influence the rate at which the drug or cosmetic agent reaches the skin surface and whether it remains on the surface (i.e. cosmetic agent) or penetrates through the stratum corneum (i.e. thera- peutic agent).
The formulator must design, therefore, a derma- tological product which not only has good physical and chemical stability and cosmetic appeal, but which also provides an optimum environment to enable the active agent to reach the intended target site. The system must be non-irritant to the skin, easily applied and removed from the skin and where appropriate, capable of incorporating buff- ers, co-solvents, antioxidants, additional polymeric stabilizers and preservatives. Thus, many formulations are very complex, multicomponent preparations containing a number of interacting surfactants, polymers and other additives. An understanding of the microstructure of such sys- tems is essential in order to optimize the formula- tion and manufacture of existing products and in the design of novel dermatological delivery systems.
In this paper, the colloidal properties of struc- tured and semisolid oil-in-water emulsions and related oil-free ternary systems used as dermatolog- ical lotions and creams are discussed. It is shown that, despite the complexity of many formulations, there are simple structural models that can be used to mimic the behaviour of the more complex multicomponent vehicles.
2. Functions of emulsifiers
components of the formulation. For example, a fatty alcohol may be described as an emulsifier, stabilizer, thickening agent or emollient depending on its perceived role in the formulation.
Dermatological emulsions, in common with all lyophobic dispersions, are thermodynamically unstable. They posses a positive interfacial free energy and will continually try to reach thermo- dynamic equilibrium by attempting to separate back into their component phases. In practice, this results in the gradual flocculation and aggregation of the dispersed phase droplets leading ultimately to a cracked or separated emulsion. To manufac- ture a consistent product with a realistic shelf-life and standard therapeutic properties, the formula- tor must attempt to delay the separation process. This can be achieved by the addition of specific mixed emulsifiers composed of ionic or non-ionic surfactants combined with fatty amphiphiles such as fatty alcohols, acids or monoglycerides (Table 1). The components of the mixture may be added separately during the high temperatures of manufacture, or alternatively they may be incorpo- rated into the formulation as a previously blended emulsifying wax (Table 2). Although these surfac- tant mixtures are traditionally described as emulsi- fiers and the term will be used in this text, it is emphasized that this term is a misnomer because they exhibit a number of functions. They stabilize oil droplets at the time of manufacture by the formation of an interfacial film, they confer long- term stability to the product by their ability to prevent the close approach of oil droplets by structuring the continuous phase and they are also used to control the rheological properties of the formulation between wide limits. The term "self bodying action", defined as the process by which
An examination of many pharmaceutical and cosmetic formulations for the skin reveals a bewil- dering number of materials, often ill-defined and classified according to their properties under general headings such as emulsifying agents, co-solvents, thickeners, humectants and emollients. Such classifications are not always satisfactory as many materials, in particular those described as emulsifiers, are capable of performing a number of functions either alone or combined with other
Table 1 Selection of commonly used fatty amphiphiles and surfactants
stable oil-in-water emulsions may be prepared of practically any desired consistency, from mobile lotions to soft or stiff creams, simply by altering the total mixed emulsifier concentration, is used to describe these combined functions.
The components of the emulsifier mixtures are of natural origin and exhibit considerable batch to batch variations, which can result in changes in the quality and consistency of the dermatological product containing them. In an attempt to counteract the effect of such variations, many formulations go for "overkill" and contain a large number of different surfactants and amphiphiles within the same preparation.
3. The gel network theory of emulsion stability
The gel network theory o f emulsion stability gives a coherent explanation for the manner in which the mixed emulsifiers and emulsifying waxes both stabilize oil droplets and control the consistency of the system between wide limits. Data used to develop the theory, including rheological evalua- tions of ternary systems and emulsions have been reviewed [5-10]. The theory relates the structure and properties of liquid and semisolid emulsions to the swelling properties of a lamellar, crystalline gel network phase formed when the mixed emulsi- fier, in excess of that required to stabilize oil droplets, interacts with continuous phase water. In order to understand practical systems better, simple models were used that mimic the mode of action of the mixed emulsifiers in more complex systems. To develop the theory, models based on (a) classical emulsion theories that describe droplet
interactions in simple emulsions and (b) the aque- ous phase behaviour of the emulsifiers over the ranges of temperature and concentration relevant to the manufacture, storage and use of the formulation.
4. Models for complex oil-in-water systems
4.1. Simple emulsions as models for complex creams
Some of the confusion over the functions of mixed emulsifiers in lotions and creams has arisen because the same emulsifier mixtures (e.g. fatty amphiphiles and ionic or non-ionic surfactants) were used by early workers to investigate the colloidal properties of very dilute, model oil-in- water emulsions. In these, the stabilizing effect of the mixed emulsifier is attributed to its ability to form a complex, monomolecular film at the oil droplet-water interface. The film introduces repul- sive forces (electrostatic, steric or hydrational) to inhibit the close approach of droplets and, if droplets do collide, a mechanical barrier to coalescence.
Schulman and Cockbain [11] related the enhanced stability of dilute oil-in-water emulsions prepared with mixtures of fatty amphiphile and ionic surfactant to the formation of molecular complexes at the oil-water interface. Although the formation of specific complexes has been ques- tioned by other workers, as has the necessity to use only ionic surfactants because good emulsions are obtained with some non-ionic mixtures, it is generally agreed that condensed and rigid films
form with such mixtures that oppose the film thinning and rupture processes of coalescence [12,131.
The effect of excess surfactant emulsifier on emulsion stability has also been investigated in simple, model emulsions, for when an oil, water and surfactant are mixed, an emulsion is only one of the many ternary phases that can exist depend- ing on the proportions of the components. The classical work of Friberg et al. [14] related a sudden increase in emulsion stability to the condi- tions in phase diagrams where a lamellar liquid crystalline phase could be separated from the emulsion. They proposed that in such emulsions, multilayers of liquid crystals concentrate at the oil droplet-water interface. These multilayers stabilize the emulsion by their ability to cause a reduction in the L o n d o n ~ a n der Vaals forces of attraction, which, combined with the high viscosity of the liquid crystalline layers, dramatically delays the processes of coalescence [15,16].
Although at first sight these models, based on single or multilayered interfacial films, might not appear to be appropriate to describe the stability and rheological properties of structured and semi- solid dermatological emulsions, there are specific occasions in the lifetime of the emulsion when they are important. For example, the existence of a strong film is particularly important for efficient emulsification during manufacture. The surfactant emulsifiers reduce the interfacial tension, making it easier for droplets to break up during the emulsification process and the viscoelastic film formed then reduces the tendency for the freshly formed droplets to recombine. The swollen lam- ellar liquid crystalline phases that sometimes form at the high temperatures of manufacture in cream formulations will form multilayers that further stabilize the newly formed droplets.
Interfacial films are also important to the sta- bility of specific emulsions in which the structural elements develop only slowly at the relatively low temperatures of storage, for only the properties of the interfacial film will protect the oil droplets from coalescence during this period of structure consolidation [3,17-19]. In fact, the larger droplet sizes in creams prepared from non-ionic emulsify- ing waxes can be related to the fact that some
droplet coalescence occurs whilst the structure of the system consolidates. In other formulations, in particular those prepared with very pure amphi- philes, the gel network phase formed after the heating and cooling cycle of preparation is unstable and formulations change from semisolid to liquid [20-22]. Again, the presence of a strong interfacial film will be the main factor in the prevention of coalescence in the mobile systems.
4.2. Structured liquid models - ternary systems
Theories based on simple model emulsions are unreal in the sense that commercial dermatological emulsions, such as lotions and semisolid creams always contain excess emulsifier over that required to form this monomolecular film. The surplus emulsifier interacts with other emulsion compo- nents, both at the droplet interfaces and in the bulk, to give complex multiphase formulations. The early observation that only those mixtures that are capable of forming lamellar phases in the bulk appear to have the ability to form strong viscoelastic films at the oil-water interface [23] is important in the light of current knowledge, for lamellar structures and strong interfacial films both depend on the ability of the molecules to pack together closely and to interact with water.
When developing the gel network theory, a valuable method of approach was to investigate first the type of interaction that occurs when the surfactant and fatty amphiphile, either separately or as a previously blended emulsifying wax are dispersed in water to form a ternary surfactant-- water-amphiphile system, and then to examine the emulsion formed when the oil is added to the formulation. It was shown that ternary systems, formed by mixing similar concentrations of mixed emulsifiers in water to those used in creams (Table 3), have similar structures and rheological properties to the corresponding creams, and such ternary systems have been extensively studied as structural models for the continuous phases of dermatological lotions and creams. The techniques used include electron and light microscopy [5,24,25], calorimetry and thermogravimetry [22,26-29], continuous shear and viscoelastic rhe- ology [6], spectroscopy [30,31] and conductivity
[32]. High- and low-angle X-ray diffraction has provided much information [28,33-38] with the use of synchrotron radiation being particularly appropriate for systems containing large amounts of water [39].
4.3. Phase behaviour of emulsifying waxes in water
The sparingly soluble amphiphiles in Table 1 exhibit marked crystalline polymorphism and are all capable of forming the so-called a-crystalline polymorph under specific conditions. In the ~- form, the hydrocarbon chains are hexagonally packed and there is rotation about the long axis of the molecule. In water, this polymorph forms the hydrated crystal in which the thickness of the water layers incorporated between the polar groups (~ 18 A) is limited by the considerable strength of the van der Waals attractive forces which balance osmotic repulsions (Fig. 1).
A characteristic feature of the a-crystalline form is that in the presence of very small quantities of ionic surfactant (i.e. molar ratios of amphiphile to
Tl"
(~, ~ Form
j-j-j-j-j-j.
7J'j'j'j"
"y Form
TTTTTT
TTTTTT
Hydrate
Fig. 1. Schematic illustration of the polymorphic structures formed by fatty alcohol amphiphiles. In excess water the s-crystals swell to from the c~-crystalline hydrate.
surfactant in the region of 10-30:1, which are the approximate proportions present in the ionic emulsifying waxes), the amount of swelling increases markedly to give a swollen a-crystalline gel phase. This gel phase is characterized by a lamellar structure of alternating bilayers of emulsi- fying wax separated by layers of water. Some amphiphiles will also swell in the presence of a non-ionic surfactant.
On heating, the gel phase transforms at a specific temperature, the transition temperature, to a lam- ellar liquid crystalline phase (Fig. 2). This phase, in which the hydrocarbon chains are molten and in a dynamic disordered state, does not swell as extensively as the low-temperature gel phase. With most of the amphiphiles used in pharmaceutical creams, the gel to liquid crystalline transition tem- peratures are well above room temperature, gen- erally between 40 and 50°C. This means that although liquid crystalline phases form in the ternary system models and emulsions at the high temperatures of manufacture, these convert to the gel phase when the system cools to the lower storage and testing temperatures.
In practice, emulsions are prepared by mixing the molten components at high temperature and then cooling to room temperature. At the high temperature, emulsion droplets are stabilized by
Water Below ( ) Above Water T c T c . . . . . . . .
the mixed interracial film at the oil droplet water interface. During the cooling process excess mixed emulsifier forms micelles or liquid crystalline phases that further stabilize the emulsion. No attempts are made to reach equilibrium, which may require protracted times, and when the tem- perature falls to below the transition temperature the liquid crystals convert to the gel phase with the simultaneous absorption of additional water, and any unreacted amphiphile precipitates to form the multicomponent gel network phase. The system sometimes changes from a milky dispersion to a structured or semisolid emulsion at the transition temperature, which is known as the "setting temperature" in commerce. Further interaction between crystalline alcohol and surfactant solution can occur on storage with the formation of addi- tional c~-crystalline gel phase. This multicomponent continuous phase is viscoelastic, and forms a gel network in which oil droplets and hydrated crystals are fixed.
Thus, after the heating and cooling cycle of preparation, the viscoelastic gel networks may be composed of at least three phases: (i) crystalline hydrates of fatty amphiphile in equilibrium with (ii) swollen lamellar a-crystalline gel phase of surfactant and fatty alcohol and (iii) free bulk water [8,35]. Remnants of this phase can be seen clearly when model ternary systems and creams stabilized by ionic emulsifying waxes are examined microscopically. Fig. 3 shows a photomicrograph of a ternary system composed of 6% cetrimide-cet- ostearyl alcohol emulsifying wax in 94% water. Distorted crystalline masses of fatty alcohol act as a focus around which multilayers of gel phase form. In the corresponding cream, multilayers of bilayer gel phase are visible surrounding the larger oil droplets and floccules of the smaller droplets.
The overall consistency of the lotion or cream and the self-bodying action of the emulsifier is related to the swelling properties and the concen- tration of the a-crystalline gel phase. The water that is incorporated between the bilayers of both the gel phase and the crystalline hydrates is essen- tially bound water and this increases the volume ratio of the dispersed phase to the "free" con- tinuous phase water, causing the system to thicken. At low emulsifier concentrations, this is sufficient
(a)
(b)
Fig. 3. Photomicrographs of (a) a cetostearyl alcohol/ centrimide/water ternary system containing 93% water, and (b) a diluted semisolid liquid paraffin-in-water emulsion stabi- lised by cetostearyl alcohol and cetrimide. Note the bilayer structures surrounding the crystalline masses of fatty alcohol in the ternary system and the large oil droplets in the emulsion.
to give a structured lotion. At higher mixed emulsi- fier concentrations, the crystalline and gel phases link together to form the gel network phases and the system becomes a semisolid cream. The self- bodying action is illustrated by the data in Fig. 4, which show an increase in apparent viscosity (i.e. the viscosity of a Newtonian fluid that would show the same shear stress at this shear rate) with mixed emulsifier concentration for lotions (2-4% mixed
G M. Eccleston / Colloids Surfaces A: Physicochem. Eng. Aspects 123 124 (1997) 169 182 175
1 . 5
/ 1] app 1.(~ / e
0.5 e e ~
I I I I i I J 2 3 4 5 6 7 Mixed Emulsifier Concentration (%w/w)
Fig. 4. Plots of the variation of apparent viscosity, ~/app (poise), versus mixed emulsifier concentration for liquid paraffin (20% w/w) in water emulsions stabilised by a cationic emulsify- ing wax (blend of cetostearyl alcohol and cetrimide at molar ratio 12 : 1 ). Systems change from structured lotions at emulsi- fier concentrations of 2-4% to creams at higher concentrations.
(2) the stability of these phases over a range of relevant storage and usage temperatures. Phase changes during the storage period will influence the rheological properties, the sta- bility and the bioavailability of the drugs and the cosmetic agents that have been incorpo- rated into the system;
(3) the thickness of the interlamellar water layers and proportion of the added water that is incorporated between them; the overall consis- tency of the product, and whether it is fluid or semisolid will depend on this; and
(4) the relative proportions of the three phases; in particular, the relative proportions of non- swollen crystalline phase, as these will also influence the appearance and other cosmetic qualities of the formulation.
It is shown in the next section how the phase behaviour of specific emulsifiers and emulsifying waxes in water can be related to the properties of the more complex lotions and creams containing them.
emulsifier) and creams (>4% mixed emulsifier) containing a cationic mixed emulsifier.
The gel network theory described above is gene- ral, and the same broad principles apply whichever surfactant and amphiphile is used. In many phar- macopoeas, the amphiphile alone is described either as a stabilizer or as a thickener, although examination of most of the formulations involved reveals that they invariably also contain ionic or non-ionic surfactants so that the so-called stabiliz- ing effect is probably due to the formation of a mixed emulsifier in situ. The fine detail of the microstructure and the formation of the gel net- work phase in a formulation, however, will vary according to the specific components of the mixed emulsifier, i.e. the type of amphiphile and the ionic or non-ionic nature of the surfactant, the concen- tration of the mixed emulsifier and the molar ratios of amphiphile to surfactant. Of particular interest when considering the bulk properties of specific formulations is to establish the following: (1) the mechanisms and kinetics involved in the
formation of these phases; the processing and manufacture of the emulsions must be adapted to encompass these;
5. Fatty alcohol mixed emulsifiers
Fatty alcohols combined with ionic or non-ionic surfactants are probably the most widely used amphiphiles as they form the basis of most of the official emulsifying waxes described in the various pharmacopoeias as well as many commercial emul- sifying waxes. The alcohol is usually a homologous admixture of cetyl and stearyl alcohols as in cetos- tearyl alcohol BP and is present in excess: tradi- tionally nine parts by weight of fatty alcohol to one part of ionic surfactant (molar ratio 12:1) or four parts of alcohol to one part of non-ionic surfactant (molar ratio approximately 20:1).
The pure long-chain alcohols exist in at least three polymorphic forms. The high-temperature ~- form separates first from the melt and is stable over a narrow temperature range. At lower temper- atures the/~-form, in which the hydrocarbon chains are non-rotating, and the tilted v-form can coexist, although the/3-form is usually in excess. Transition temperatures are lower with homologous admix- tures such as cetostearyl alcohol, and in the pres- ence of water where they exhibit limited swelling
to form crystalline hydrates (cf. Fig. 1). Thus, the pure cetyl or stearyl alcohols in water may be in the/~ and 7 crystalline forms at room temperature (25°C) whilst the a-modification is the stable form with mixed homologue alcohols such as cetos- tearyl alcohol.
5.1. Fatty alcohols/ionic surfactants
Fatty alcohols in the presence of relatively small quantities of ionic surfactant exhibit phenomenal swelling. Fig. 5 shows X-ray data obtained from a synchrotron radiation source for a cetrimide emul- sifying wax in 93% water (the model ternary system), where the interlamellar water layer spacing is approximately 500 A, that is, a factor of 10 times greater than the bilayer spacing of about 50A [39]. Similar spacings have been observed in the corresponding cream formulations, and the bilayers are visible under the light micro- scope (cf. Fig. 3). The anionic emulsifying waxes appear to swell excessively in a similar manner [35]. The extent of the swelling is emphasized by the schematic diagram in Fig. 6, which shows the emulsion bilayers drawn to scale. The swelling mechanism is electrostatic in nature. The charged surfactant inserts into the a-crystals of the amphi-
11 - -
9 - -
7 _
5
3 - -
1 - -
~__ 550A
1st Order
2nd Order
3rd Order ~.. ~--.- 4th Order
0.010 0.020 0.030
I
0.040
phile, and the charges created at the surface of the bilayers significantly increases the forces of repul- sion between them.
Provided that the fatty alcohol is in the :~- crystalline form, the viscoelastic gel network phase is stable and will form spontaneously at room temperature, i.e. a heating and cooling cycle is not required. The swelling of fatty alcohols in the presence of an ionic surfactant and excess water can sometimes be observed microscopically. Fig. 7 shows the interaction between aqueous cetrimide solution and cetostearyl alcohol previously recrys- tallized on a microscope slide. As soon as the surfactant solution makes contact with the alcohol crystals, the sharp edges of the alcohol become progressively less well defined. As the e-crystals swell, the lamellar phase spreads over the field of view, giving the appearance of a linked system. Stable ternary systems and oil-in-water creams can actually be prepared at room temperature using a crystalline mixed homologue fatty alcohol, although the prolonged mixing necessary does not make this a practical proposition [40].
The stability of the gel phase prepared with fatty alcohols depends on the polymorphism of the long-chain alcohol. The transition temperature must be lowered sufficiently for the :~-crystal to be the stable form at room temperature [5,20 22]. This explains why pure fatty alcohols do not make stable emulsions or ternary systems, while homo- logue admixtures provides a system stable over many years. The surfactant is not observed in microscopic experiments to interact with the pure alcohol at room temperature and the c~-crystalline gel phase present initially in systems that have been prepared by a heating and cooling cycle transforms to non-swelling /~- or 7-crystals and water (Fig. 8). As the swollen gel phase dehy- drates, the system changes from a semisolid to a milky liquid. The gradual transformation to a liquid, which is not always obvious from the properties of the freshly prepared system, can take protracted times (several weeks) with serious bio- logical and economic consequences.
S (l/A)
Fig. 5. Small angle X-ray diffraction data (synchrotron radia- tion source) for the model cetrimide/cetostearyl alcohol/water ternary system containing 94% water.
5.2. Fatty alcohols~non-ionic surfactants
Mixed emulsifiers and emulsifying waxes com- posed of fatty alcohols and non-ionic surfactants
Fig. 6. Schematic diagram of a typical multiphase oil-in-water cream stabilised by an ionic emulsifying wax to illustrate (to scale) the thickness of the interlamellar water layers. • fatty alcohol; O ionic surfactant.
(a) (a)
(b)
Fig. 7. Photomicrographs of the swelling and interaction of cetostearyl alcohol in the presence of surfactant solution on a microscope slide at 25 ° C. (a) globules of crystalline cetostearly alcohol; (b) 1 h after flooding the slide with 5% surfactant solution.
(b)
Fig. 8. Photomicrographs of (a) a ternary system, and (b) an emulsion (between crossed polars) prepared with pure cetyl alcohol and six months ageing, when the gel network phases first formed immediately after manufacture have broken down to platey crystals. Both systems have changed from semisolid creams to mobile lotions during this period (see Fig. 4).
are often preferred in dermatological lotions and creams because of their comparative lack of irrita- bility to the skin and their compatibility with ionic drug or cosmetic agents. The official non-ionic surfactants of the British and the North American pharmacopoeas, cetomacrogol 1000 and polysor- bate, respectively, both contain 20-24 polyoxy- ethylene (POE) chains as the hydrophilic component of the molecule. The fatty alcohols swell in the presence of these non-ionic surfactants, although both the mechanism and the time scale of swelling is different from the ionic systems described above. In non-ionic systems, the surfac- tant is interpositioned among the alcohol mole- cules and the swelling of the ~-crystals of alcohol is due to hydration of the polyoxyethylene chains of the surfactant which are oriented and extended into the interlamellar water layers [27,28,34, 37, 39]. Fig. 9 shows X-ray data for a cetomacrogol emulsifying wax in 93% water (the model ternary system), where the interlamellar water layer spac- ing is approximately 110 A, that is approximately twice the bilayer spacing of about 50 A [39]. The thickness of the water layers is approximately twice the length of two POE chains extended in the zig- zag conformation and stabilization of the non- ionic gel phase is by steric repulsions (Fig. 10).
150-
130- ~ _ _
110 -
90
70
50-
3°1 1 0
I
0.006
16oA 1 st Order
2nd Order
( r r
0.010 0.030
S (l/A)
Fig. 9. Small angle X-ray diffraction data (synchrotron radia- tion source) for a model cetomacrogol/cetostearyl alcohol/water ternary system containing 90% water.
- . . . . . ~ z : 1 - - - I=:~__~ Oil Z Interlamellar ~ 22~ In ter larnel lar ~ Drople t ~ Water - - ~ ~ Water - - o - -
Creams containing non-ionic emulsifying waxes often show considerable structural changes on stor- age, sometimes changing from a milky liquid to a semisolid. Changes in the rheological properties are undesirable, not only from a cosmetic viewpoint, but also because variable bioavailability profiles may result. These structural changes occur because the polyoxyethylene chains are not very soluble in water at the high temperature of preparation, but become more soluble as systems cool to below the transition temperature when the hydrocarbon chains crystallize. This means that the lamellar gel phase is only partially formed when the emulsion cools, so that the system is often mobile immediately after prepara- tion. On storage, the increased solubility of the POE groups allows additional lamellar gel phase to form, although this occurs very slowly because of the crystalline nature of the chains. The emulsions grad- ually thicken and partially interacted emulsifier masses visible microscopically in the freshly prepared system disappear from the continuous phase as hydration proceeds and they form additional gel phase [40].
6 . F a t t y a c i d m i x e d e m u l s i f i e r s
6.1. Fatty acid/ionic surfactant combinations
Stearic acid is widely used as a component of the so-called "vanishing creams" which are used
in cosmetics as hand creams and foundation creams. The cream, which usually has an attractive, pearlescence sheen, appears almost to vanish during application, leaving a matt, non-greasy residue on the skin. The traditional stearate cream is not an emulsion at all, but a ternary system composed of stearic acid, a stearate soap and water (Table4). The stearate soap is formed in situ during the manufacture of the product by the partial neutralization of some of the fatty acid (10-25%) with alkali, traditionally triethanolam- ine, to produce triethanolamine stearate. Sodium hydroxide or potassium hydroxide is also used in some formulations to produce sodium stearate or potassium stearate soaps. When an oil phase is present, the stearic acid and its soap function as a mixed emulsifier to stabilize and control the consis- tency of the preparation. In some formulations additional ionic surfactants are added to augment those produced in situ; non-ionic surfactants do not appear to perform the same function. A char- acteristic feature of all stearate creams is their marked susceptibility to processing variables. For example, a much stifler cream is obtained if mixing is stopped at the setting temperature and the cream allowed to cool undisturbed than when the system is mixed until cool.
The most widely used stearic acid in commerce is not pure, but a "triple-pressed" mixture com- posed of approximately 55% palmitic acid (C16) and 45% stearic acid (Cls) with traces of other unsaturated and saturated fatty acids present. The pearly appearence and properties of stearate creams can be related to the polymorphism and phase behaviour of the mixed homologue stearic acid-surfactant combinations which are sometimes
Table 4 Typical stearate cream formulations
Ternary system (e.g. vanishing cream)
Emulsion (e.g. night cream)
Stearic acid (g) 22 Triethanolamine (g) 1.5 Water (g) 76.5 White soft paraffin (g) Liquid paraffin (g)
14 1.5
44.5 20 20
described as acid-soaps in the literature [41]. The saturated long-chain fatty acids exhibit marked polymorphism, with the polymorphs described as the A, B, C and E forms. This nomenclature is based on differences in the angle of tilt of the molecules towards the end-group plane as detected by X-ray diffraction. Polymorph A shows the smallest tilt and C the highest [42-44]. The C polymorph of pure and mixed homologous stearic acid is the most stable. It crystallizes first from the melt and polymorphs A, B, and E transform to the C form on heating. However, the crystallization is very sensitive the nature of the crystallization solvent and to the conditions of crystallization such as cooling rates and the extent of agitation [45].
The acid-soap formed by the partial neutraliza- tion free fatty acid with triethanolamine swells in water to form lamellar gel phases. These exist in equilibrium with crystals of stearic acid and water [35]. These swollen lamellar phases differ from the swollen e-crystalline phases of the fatty alcohols in two important respects. First, the proportion of the crystalline phase in equilibrium with the gel phase is greater, with the translucent nature of the precipitated stearic acid crystals giving the cream an attractive pearly shean. Second, the swollen crystalline gel phase is not only sensitive to temper- ature but also to processing variables, in a manner that parallels the instability of the C polymorph. In some systems, the swollen lamellar structures appear to be metastable and under pressure convert into non-swollen structures. This probably explains the sensitivity of stearate systems to processing variables; such destabilization may also occur after application to the skin [46]. Traditionally, small quantities of fatty alcohol such as cetyl alcohol are considered to stabilize the system, presumably by forming extra swollen gel!
7. Self-emulsifying glyeeryl monoesters
Glyceryl monoesters, prepared by the esterifica- tion of glycerol with fatty acids, are used as emulsifying agents, stabilizers and thickeners in a variety of pharmaceutical, cosmetic and food emulsions. Glyceryl monostearate and glyceryl monooleate are the most common derivatives used
in dermatological formulations and standards for both are given in the various international pharma- copoeas. The fatty acids used in the esterification are not pure substances but generally of mixed homologue composition; thus the commercial grades of the glyceryl monoesters are generally homologue admixtures of mainly C14-C18 mono- glycerides together with variable amounts of di- and triglycerides, free fatty acids and their salts and traces of free alcohols such as glycerol. The name of the ester merely indicates the predominant acid in the mixture. For example, the specification for Glyceryl Monostearate in the USPNF XVII states that it must consist of not less than 90% of monoglycerides, chiefly glyceryl monostearate and glyceryl monopalmitate. In contrast, the mono- graph in the European Pharmacopoea describes Glyceryl Monstearate 40-50 as a mixture of mono-, di- and triglycerides of stearic and palmitic acids which contain not less than 40% and more than 50% of monglycerides calculated as the monstearate.
The amphiphilic glyceryl monoesters, which alone are poor oil-in-water emulsifiers, are described as called "non-self-emulsifying" grades in the various pharmacopoeas. The so-called "self- emulsifying" grades, formed when about 5% of ionic or non-ionic surfactant is added, are essen- tially glyceryl monoester emulsifying waxes for they form semisolid ternary systems and creams when dispersed in water and exhibit a self-body- ing action.
The mixed homologue monoglycerides, which have been extensively studied in relation to food emulsions by Krog, Larsson and co-workers [47- 50], show similar crystalline polymorphism to the fatty alcohols discussed above. The e-form, in which the hydrocarbon chains are packed in the hexagonal lattice, is the least stable of the poly- morphs but is stabilized in water, where it shows limited swelling. The introduction of a small amount of charged surfactant, either by the neu- tralization of some of the free fatty acid component of the monoester by alkali or by the addition of surface-active agents as in the self-emulsifying grades, permits the e-crystalline gel phase to swell almost indefinitely owing to the charge repulsion
and osmotic repulsions between the bilayers (cf fatty alcohols).
In common with the fatty acids, the stability of the swollen e-crystalline gel phase even with mixed homologue monoglycerides is poor. Mechanical disruption, for example by stirring, transforms the swollen gel phase into the fl-polymorphic form, which is accompanied by the exclusion of water from the crystal lattice [47, 51 ]. As this occurs, the system will convert from a semisolid or structured liquid into a milky liquid. Thus manufacturing variables, such as heating and cooling rates and mixing conditions, can affect the structure and the rheology of lotions and creams prepared from monoglycerides. Traditionally, as with the stearate creams discussed above, small quantities of fatty alcohol such as cetyl alcohol are considered to stabilize the system.
As crystallization into the e-form is a prere- quisite for the formation of the gel phases, emulsi- fiers that are non-polymorphic and stable in the e-modification, such as lactylated monoglycerides, acetylated monoglycerides and propylene glycol monoglycerides, have been used to obtain gels exhibiting long-term stability [52].
8. Phospholipids-natural emulsifying waxes?
The phospholipids are complex molecules of biological origin that occur in most cells and small amounts are present in vegetable and animal oils and fats. The commercially available lecithins used in pharmaceutical, cosmetic and food products are generally complex mixtures of phospholipids (cf. Table 5) composed principally of neutral phospho- lipids, phosphatidylcholine and phosphadidyl- ethanolamine, and negatively charged lipids, phos- phadidylserine, phosphadidylinositol and phos- phatidic acid, in various ratios depending on their source (either animal, e.g. yolk, or plant, e.g. soybean) and the extent of purification. The fatty acid composition of the molecules also varies markedly with the source of the material and from batch to batch [53].
The fact that the phospholipids can form bilayer phases that incorporate water is the basis of much current knowledge about cell membranes and has
led to claims that the lecithins, when incorporated into dermatological formulations, are in some way compatible with the lipids of the stratum corneum which are also organized into bilayer phases. In addition to their emulsifying functions, the leci- thins are claimed to moisturize the skin and to impart emolliency.
The mixture of neutral and charged lipids mean that the lecithins can be considered to consist of mixed emulsifiers composed of non-swelling neut- ral amphiphilic lipids combined with negatively charged surface-active lipids, i.e. a natural emulsi- fying wax. Both the a-crystalline gel and the more disordered liquid crystalline forms can swell to incorporate various quantities of water. With com- mercial lecithins the transition temperatures, which are influenced by the chain length and by the degree of saturation or branching of the lipids, are low, probably well below zero [54], so that it is the liquid crystalline phase that stabilizes the emul- sion. Thus the emulsifier does not structure the emulsion by a self-bodying mechanism, but rather imparts stability by the formation of multilayers at the droplet interface. Rydhag and co-workers [53,55,56] investigated the stability of emulsions prepared with different batches of lecithin and found that the most stable emulsions were those prepared with batches containing the greatest content of negatively charged lipids, because the repulsive forces at the surface of the bilayers increased swelling. Pure phosphadidyl choline yielded the least stable emulsion based on droplet size. The emulsifying properties of some batches could be improved by the addition of ionic surfactant.
9. Evaporation of complex systems
It is not always realised that emulsion destabili- zation often occurs during use. For example, when a dermatological emulsion is rubbed on to the skin, water evaporates and oil droplets coalesce. Phase changes may accompany these phenomena. Drug availability will change as the vehicle com- position alters through the resultant modification of thermodynamic activity and diffusion coeffi- cients. The majority of investigations concerning in vitro vehicle effects on drug release and absorp- tion (reviewed by Idsen [2] and Barry [3]) are unrealistic in that the original formulation is studied and possible structural changes are ignored. The actual drug delivery system is, in fact, the partially evaporated emulsion and the final film, rather than the original system as formu- lated. The extent of skin hydration will be influ- enced both by water donated during evaporation and by the occlusivity of the final film.
On application to the skin as a thin film, the composition of a cream will change as water and other volatile solvents evaporate. The use of simul- taneous evaporation and X-ray diffraction meas- urements to monitor microstructural changes that occur when thin-film layers of emulsion evaporate have demonstrated that the evaporation processes, which are kinetically driven, are extremely sensitive to the structure of the lamellar gel network [57, 58].
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