Coarse Dispersion Martin

P1: Trim: 8.375in × 10.
875in
LWBK401-17 LWW-Sinko-educational November 4, 2009 1:36
17 COARSE DISPERSIONS
At the conclusion of this chapter 6 Describe the approaches commonly used in the prepara-
CHAPTER OBJECTIVES the student should be able to: tion of physically stable suspensions.
1 Describe what pharmaceutical suspensions are and what 7 Define pharmaceutical emulsion and emulsifying agent
roles they play in the pharmaceutical sciences. and identify the main types of emulsions.
2 Discuss the desirable qualities of pharmaceutical sus- 8 Discuss the four classifications of pharmaceutical emul-
pensions. sion instability.
3 Discuss the factors that affect the stability of suspensions 9 Understand semisolids, thixotropic properties, syneresis,
and explain flocculation. and swelling.
4 Describe settling and sedimentation theory and calculate 10 Classify pharmaceutical semisolids.
sedimentation rates. 11 Describe coarse dispersions and give examples.
5 Define and calculate the two useful sedimentation par-
ameters, sedimentation volume and degree of flocculation.
Particulate systems have been classified on the basis of designed for dermatologic, cosmetic, and protective pur-
size into molecular dispersions (Chapter 5), colloidal systems poses. The concentration of dispersed phase may exceed
(Chapter 16), and coarse dispersions (this chapter). This chap- 20%. Parenteral suspensions contain from 0.5% to 30% of
ter attempts to provide the pharmacist with an insight into the solid particles. Viscosity and particle size are significant fac-
role of physics and chemistry in the research and develop- tors because they affect the ease of injection and the avail-
ment of the several classes of coarse dispersions. The theory ability of the drug in depot therapy.
and technology of these important pharmaceutical classes are An acceptable suspension possesses certain desirable
based on interfacial and colloidal principles, micromeritics, qualities, including the following. The suspended material
and rheology (Chapters 15, 16, 18, and 19, respectively). should not settle rapidly; the particles that do settle to the
bottom of the container must not form a hard cake but should
be readily redispersed into a uniform mixture when the con-
SUSPENSIONS tainer is shaken; and the suspension must not be too viscous
to pour freely from the orifice of the bottle or to flow through
A pharmaceutical suspension is a coarse dispersion in which a syringe needle. In the case of an external lotion, the product
insoluble solid particles are dispersed in a liquid medium. must be fluid enough to spread easily over the affected area
The particles have diameters for the most part greater than and yet must not be so mobile that it runs off the surface to
0.1 μm, and some of the particles are observed under the which it is applied; the lotion must dry quickly and provide
microscope to exhibit Brownian movement if the dispersion an elastic protective film that will not rub off easily; and it
has a low viscosity. must have an acceptable color and odor.
Examples of oral suspensions are the oral antibiotic It is important that the characteristics of the dispersed
syrups, which normally contain 125 to 500 mg per 5 mL phase be chosen with care so as to produce a suspension hav-
of solid material. When formulated for use as pediatric ing optimum physical, chemical, and pharmacologic prop-
drops, the concentration of suspended material is correspond- erties. Particle-size distribution, specific surface area, inhi-
ingly greater. Antacid and radiopaque suspensions gener- bition of crystal growth, and changes in polymorphic form
ally contain high concentrations of dispersed solids. Exter- are of special significance, and the formulator must ensure
nally applied suspensions for topical use are legion and are that these and other properties1−3 do not change sufficiently
K E Y C O N C E P T SUSPENSIONS
Suspensions contribute to pharmacy and medicine by supplying parenteral administration of insoluble drugs. Therefore, pharma-
insoluble and what often would otherwise be distasteful sub- ceutical suspensions can be classified into three groups: orally
stances in a form that is pleasant to the taste, by providing a administered mixtures, externally applied lotions, and injectable
suitable form for the application of dermatologic materials to preparations.
the skin and sometimes to the mucous membranes, and for the
410
P1: Trim: 8.375in × 10.875in
CHAPTER 17: COARSE DISPERSIONS 411
during storage to adversely affect the performance of the When the surface area is 107 cm2 ,
suspension. Finally, it is desirable that the product contain
G 2 = 100 × 107 = 109 ergs/cm2
readily obtainable ingredients that can be incorporated into
the mixture with relative ease by the use of standard methods The change in the free energy, ΔG21 , is 109 − 105 ∼
= 109 erg/cm2 .
9
and equipment. The free energy has been increased by 10 , which makes the system
more thermodynamically unstable.
The remainder of this section will be devoted to a dis-
cussion of some of the properties that provide the desirable
characteristics just enumerated. To approach a stable state, the system tends to reduce the
For pharmaceutical purposes, physical stability of suspen- surface free energy; equilibrium is reached when G = 0.
sions may be defined as the condition in which the particles This condition can be accomplished, as seen from equation
do not aggregate and in which they remain uniformly dis- (17–1), by a reduction of interfacial tension, or it can be
tributed throughout the dispersion. Because this ideal situ- approached by a decrease of the interfacial area. The lat-
ation is seldom realized, it is appropriate to add that if the ter possibility, leading to flocculation or aggregation, can be
particles do settle, they should be easily resuspended by a desirable or undesirable in a pharmaceutical suspension, as
moderate amount of agitation. considered in a later section.
The interfacial tension can be reduced by the addition
of a surfactant but cannot ordinarily be made equal to zero.
INTERFACIAL PROPERTIES OF SUSPENDED A suspension of insoluble particles, then, usually possesses
PARTICLES a finite positive interfacial tension, and the particles tend to
flocculate. An analysis paralleling this one could also be made
Little is known about energy conditions at the surfaces of for the breaking of an emulsion.
solids, yet knowledge of the thermodynamic requirements is The forces at the surface of a particle affect the degree
needed for the successful stabilization of suspended particles. of flocculation and agglomeration in a suspension. Forces of
Work must be done to reduce a solid to small particles attraction are of the London–van der Waals type; the repulsive
and disperse them in a continuous medium. The large sur- forces arise from the interaction of the electric double layers
face area of the particles that results from the comminution surrounding each particle. The formation of the electric dou-
is associated with a surface free energy that makes the sys- ble layer is considered in detail in Chapter 15, which deals
tem thermodynamically unstable, by which we mean that the with interfacial phenomena. The student is advised to review,
particles are highly energetic and tend to regroup in such a at this point, the section dealing with the electrical properties
way as to decrease the total area and reduce the surface free of interfaces because particle charge, electric double-layer
energy. The particles in a liquid suspension therefore tend to formation, and zeta potential are all relevant to the present
flocculate, that is, to form light, fluffy conglomerates that are topic.
held together by weak van der Waals forces. Under certain The potential energy of two particles is plotted in Figure
conditions—in a compacted cake, for example—the particles 17–1 as a function of the distance of separation. Shown are
may adhere by stronger forces to form what are termed aggre- the curves depicting the energy of attraction, the energy of
gates. Caking often occurs by the growth and fusing together repulsion, and the net energy, which has a peak and two min-
of crystals in the precipitates to produce a solid aggregate. ima. When the repulsion energy is high, the potential barrier
The formation of any type of agglomerate, either floccules is also high, and collision of the particles is opposed. The sys-
or aggregates, is taken as a measure of the system’s tendency tem remains deflocculated, and, when sedimentation is com-
to reach a more thermodynamically stable state. An increase plete, the particles form a close-packed arrangement with the
in the work, W, or surface free energy, G, brought about smaller particles filling the voids between the larger ones.
by dividing the solid into smaller particles and consequently Those particles lowest in the sediment are gradually pressed
increasing the total surface area, A, is given by together by the weight of the ones above; the energy barrier is
thus overcome, allowing the particles to come into close con-
G = γ SL · A (17–1) tact with each other. To resuspend and redisperse these parti-
cles, it is again necessary to overcome the high-energy barrier.
where γ S L is the interfacial tension between the liquid
Because this is not easily achieved by agitation, the particles
medium and the solid particles.
tend to remain strongly attracted to each other and form a
EXAMPLE 17–1 hard cake. When the particles are flocculated, the energy bar-
Surface Free Energy rier is still too large to be surmounted, and so the approaching
Compute the change in the surface free energy of a solid in a sus-
particle resides in the second energy minimum, which is at a
pension if the total surface is increased from 103 to 107 cm2 . Assume distance of separation of perhaps 1000 to 2000 Å. This dis-
that the interfacial tension between the solid and the liquid medium, tance is sufficient to form the loosely structural flocs. These
γ SL , is 100 dynes/cm. concepts evolve from the Derjaguin and Landau, Verwey
The initial free energy is and Overbeek (DLVO) theory for the stability of lyopho-
G 1 = 100 × 103 = 105 ergs/cm2 bic sols. Schneider et al.4 prepared a computer program for
P1: Trim: 8.375in × 10.875in
412 MARTIN’S PHYSICAL PHARMACY AND PHARMACEUTICAL SCIENCES
phase and dispersion medium, respectively, g is the acceler-

ation due to gravity, and ηo is the viscosity of the dispersion
medium in poise.
Dilute pharmaceutical suspensions containing less than
about 2 g of solids per 100 mL of liquid conform roughly to
these conditions. (Some feel that the concentration must be
less than 0.5 g/100 mL before Stokes’s equation is valid.) In
dilute suspensions, the particles do not interfere with one
another during sedimentation, and free settling occurs. In
most pharmaceutical suspensions that contain dispersed par-
ticles in concentrations of 5%, 10%, or higher percentages,
the particles exhibit hindered settling. The particles interfere
with one another as they fall, and Stokes’s law no longer
applies.
Under these circumstances, some estimation of physical
stability can be obtained by diluting the suspension so that
it contains about 0.5% to 2.0% w/v of dispersed phase. This
is not always recommended, however, because the stability
picture obtained is not necessarily that of the original sus-
pension. The addition of a diluent may affect the degree of
flocculation (or deflocculation) of the system, thereby effec-
tively changing the particle-size distribution.
To account for the nonuniformity in particle shape and size
invariably encountered in real systems. We can write Stokes’s
Fig. 17–1. Potential energy curves for particle interactions in sus- equation in other forms. One of the proposed modifications
pension. (From A. Martin, J. Pharm. Sci. 50, 514, 1961. With permis- is5
sion.)
v = v
n
(17–3)
calculating the repulsion and attraction energies in pharma-
ceutical suspensions. They showed the methods of handling where v is the rate of fall at the interface in cm/sec and v is
the DLVO equations and the careful consideration that must the velocity of sedimentation according to Stokes’s law. The
be given to the many physical units involved. Detailed exam- term ε represents the initial porosity of the system, that is,
ples of calculations were given. the initial volume fraction of the uniformly mixed suspension,
To summarize, flocculated particles are weakly bonded, which varies from zero to unity. The exponent n is a measure
settle rapidly, do not form a cake, and are easily resuspended; of the “hindering” of the system. It is a constant for each
deflocculated particles settle slowly and eventually form a system.
sediment in which aggregation occurs with the resultant for-
mation of a hard cake that is difficult to resuspend. EXAMPLE 17–2
The average particle diameter of calcium carbonate in aqueous sus-
pension is 54 μm. The densities of CaCO3 and water, respectively,
SETTLING IN SUSPENSIONS are 2.7 and 0.997 g/cm3 . The viscosity of water is 0.009 poise at
25◦ C. Compute the rate of fall v for CaCO3 samples at two differ-
ent porosities, 1 = 0.95 and 2 = 0.5. The n value is 19.73.
As mentioned earlier, one aspect of physical stability in
From Stokes’s law, equation (17–2),
pharmaceutical suspensions is concerned with keeping the
particles uniformly distributed throughout the dispersion. (54 × 10−4 )2 (2.7 − 0.997)981
v = = 0.30 cm/sec
Although it is seldom possible to prevent settling completely 18 × 0.009
over a prolonged period of time, it is necessary to consider Taking logarithms on both sides of equation (17–3), we obtain ln
the factors that influence the velocity of sedimentation. v = ln v + n ln .
For 1 = 0.95,
Theory of Sedimentation ln v = −1.204 + [19.73(−0.051)] = −2.210
The velocity of sedimentation is expressed by Stokes’s law: v = 0.11 cm/sec
d 2 (ρs − ρo )g Analogously, for 2 = 0.5, v = 3.5 × 10−7 cm/sec. Note that at
v = (17–2)
18ηo low porosity values (i.e., 0.5, which corresponds to a high concentra-
tion of solid in suspension), the sedimentation is hindered, leading
where v is the terminal velocity in cm/sec, d is the diameter of to small v values. On the other hand, when the suspension becomes
the particle in cm, ρ s and ρ o are the densities of the dispersed infinitely diluted (i.e., = 1), the rate of fall is given by v = v. In
P1: Trim: 8.375in × 10.875in
the present example, if = 1, one size of particle is present), and the supernatant remains

v = 0.3 × 1 19.73
= 0.3 cm/sec
turbid for a considerably longer period of time. Whether the
supernatant liquid is clear or turbid during the initial stages
which is the Stokes-law velocity. of settling is a good indication of whether the system is floc-
culated or deflocculated, respectively.
According to Hiestand,7 the initial rate of settling of floc-
Effect of Brownian Movement culated particles is determined by the floc size and the poros-
ity of the aggregated mass. Subsequently, the rate depends
For particles having a diameter of about 2 to 5 μm (depending
on compaction and rearrangement processes within the sed-
on the density of the particles and the density and viscosity
iment. The term subsidence is sometimes used to describe
of the suspending medium), Brownian movement counteracts
settling in flocculated systems.
sedimentation to a measurable extent at room temperature by
keeping the dispersed material in random motion. The critical
radius, r, below which particles will be kept in suspension by Sedimentation Parameters
kinetic bombardment of the particles by the molecules of the
suspending medium (Brownian movement) was worked out Two useful parameters that can be derived from sedimenta-
by Burton.6 tion (or, more correctly, subsidence) studies are sedimenta-
It can be seen in the microscope that Brownian movement tion volume, V, or height, H, and degree of flocculation.
of the smallest particles in a field of particles of a pharma- The sedimentation volume, F, is defined as the ratio of the
ceutical suspension is usually eliminated when the sample is final, or ultimate, volume of the sediment, Vu , to the original
dispersed in a 50% glycerin solution, having a viscosity of volume of the suspension, Vo , before settling. Thus,
about 5 centipoise. Hence, it is unlikely that the particles in
F = Vu /Vo (17–4)
an ordinary pharmaceutical suspension containing suspend-
ing agents are in a state of vigorous Brownian motion. The sedimentation volume can have values ranging from
less than 1 to greater than 1. F is normally less than 1, and in
this case, the ultimate volume of sediment is smaller than the
Sedimentation of Flocculated Particles
original volume of suspension, as shown in Figure 17–2a,
When sedimentation is studied in flocculated systems, it is in which F = 0.5. If the volume of sediment in a flocculated
observed that the flocs tend to fall together, producing a dis- suspension equals the original volume of suspension, then
tinct boundary between the sediment and the supernatant liq- F = 1 (Fig. 17–2b). Such a product is said to be in “floccula-
uid. The liquid above the sediment is clear because even the tion equilibrium” and shows no clear supernatant on standing.
small particles present in the system are associated with the It is therefore pharmaceutically acceptable. It is possible for
flocs. Such is not the case in deflocculated suspensions hav- F to have values greater than 1, meaning that the final volume
ing a range of particle sizes, in which, in accordance with of sediment is greater than the original suspension volume.
Stokes’s law, the larger particles settle more rapidly than the This comes about because the network of flocs formed in
smaller particles. No clear boundary is formed (unless only the suspension is so loose and fluffy that the volume they
Fig. 17–2. Sedimentation volumes produced by adding varying amounts of flocculating agent.
Examples (b) and (c) are pharmaceutically acceptable.
P1: Trim: 8.375in × 10.875in
are able to encompass is greater than the original volume of deflocculated) so that, ideally, no settling occurs. In reality,
suspension. This situation is illustrated in Figure 17–2c, in some degree of sedimentation will usually take place. The
which sufficient extra vehicles have been added to contain “shear-thinning” property of these vehicles does, however,
the sediment. In example shown, F = 1.5. facilitate the re-formation of a uniform dispersion when shear
The sedimentation volume gives only a qualitative account is applied.
of flocculation because it lacks a meaningful reference point.7 A disadvantage of deflocculated systems, mentioned ear-
A more useful parameter for flocculation is β, the degree of lier, is the formation of a compact cake when the particles
flocculation. eventually settle. It is for this reason that the formulation
If we consider a suspension that is completely defloccu- of flocculated suspensions has been advocated.8 Optimum
lated, the ultimate volume of the sediment will be relatively physical stability and appearance will be obtained when the
small. Writing this volume as V∞ , based on equation (17–4), suspension is formulated with flocculated particles in a struc-
we have tured vehicle of the hydrophilic colloid type. Consequently,
most of the subsequent discussion will be concerned with
F∞ = V∞ /Vo (17–5)
this approach and the means by which controlled floccula-
where F∞ is the sedimentation volume of the deflocculated, tion can be achieved. Whatever approach is used, the product
or peptized, suspension. The degree of flocculation, β, is must (a) flow readily from the container and (b) possess a
therefore defined as the ratio of F to F∞ , or uniform distribution of particles in each dose.
β = F/F∞ (17–6)
Wetting of Particles
Substituting equations (17–4) and (17–5) in equation
(17–6), we obtain The initial dispersion of an insoluble powder in a vehicle is
an important step in the manufacturing process and requires
Vu /Vo
β= = Vu /V∞ (17–7) further consideration. Powders sometimes are added to the
V∞ /Vo vehicle, particularly in large-scale operations, by dusting on
The degree of flocculation is a more fundamental param- the surface of the liquid. It is frequently difficult to disperse
eter than F because it relates the volume of flocculated sedi- the powder owing to an adsorbed layer of air, minute quan-
ment to that in a deflocculated system. We can therefore say tities of grease, and other contaminants. The powder is not
that readily wetted, and although it may have a high density, it
Ultimate sediment volume of flocculated suspension floats on the surface of the liquid. Finely powdered substances
β= are particularly susceptible to this effect because of entrained
Ultimate sediment volume of deflocculated suspension
air, and they fail to become wetted even when forced below
EXAMPLE 17–3 the surface of the suspending medium. The wettability of a
powder can be ascertained easily by observing the contact
Compute the sedimentation volume of a 5% w/v suspension of mag-
angle that powder makes with the surface of the liquid. The
nesium carbonate in water. The initial volume is Vo = 100 mL and
the final volume of the sediment is Vu = 30 mL. If the degree of floc- angle is approximately 90◦ when the particles are floating
culation is β = F/F∞ = 1.3, what is the deflocculated sedimentation well out of the liquid. A powder that floats low in the liquid
volume, F∞ ? has a lesser angle, and one that sinks obviously shows no
We have contact angle. Powders that are not easily wetted by water
F = 30/100 = 0.30 and accordingly show a large contact angle, such as sulfur,
F∞ = F/β = 0.30/1.3 = 0.23 charcoal, and magnesium stearate, are said to be hydropho-
bic. Powders that are readily wetted by water when free of
adsorbed contaminants are called hydrophilic. Zinc oxide,
talc, and magnesium carbonate belong to the latter class.
FORMULATION OF SUSPENSIONS Surfactants are quite useful in the preparation of a suspen-
sion in reducing the interfacial tension between solid particles
The approaches commonly used in the preparation of physi- and a vehicle. As a result of the lowered interfacial tension,
cally stable suspensions fall into two categories—the use of a the advancing contact angle is lowered, air is displaced from
structured vehicle to maintain deflocculated particles in sus- the surface of particles, and wetting and deflocculation are
pension, and the application of the principles of flocculation promoted. Schott et al.9 studied the deflocculating effect of
to produce flocs that, although they settle rapidly, are easily octoxynol, a nonionic surfactant, in enhancing the dissolu-
resuspended with a minimum of agitation. tion rate of prednisolone from tablets. The tablets break up
Structured vehicles are pseudoplastic and plastic in nature; into fine granules that are deflocculated in suspension. The
their rheologic properties are discussed in Chapter 19. As deflocculating effect is proportional to the surfactant con-
we shall see in a later section, it is frequently desirable centration. However, at very high surfactant concentration,
that thixotropy be associated with these two types of flow. say, 15 times the critical micelle concentration, the surfac-
Structured vehicles act by entrapping the particles (generally tant produces extensive flocculation. Glycerin and similar
P1: Trim: 8.375in × 10.875in
Fig. 17–3. Caking diagram, showing the floc-

culation of a bismuth subnitrate suspension
by means of the flocculating agent monoba-
sic potassium phosphate. (From A. Martin
and J. Swarbrick, in Sprowls’ American
Pharmacy, 6th Ed., Lippincott, Philadelphia,
Concentration KH2PO4
1966, p. 205. With permission.)
hygroscopic substances are also valuable in levigating the adjacent particles so as to link them together in a loosely
insoluble material. Apparently, glycerin flows into the voids arranged structure.
between the particles to displace the air and, during the mix- If we disperse particles of bismuth subnitrate in water,
ing operation, coats and separates the material so that water we find that, based on electrophoretic mobility studies, they
can penetrate and wet the individual particles. The disper- possess a large positive charge, or zeta potential. Because
sion of particles of colloidal gums by alcohol, glycerin, and of the strong forces of repulsion between adjacent particles,
propylene glycol, allowing water to subsequently penetrate the system is peptized or deflocculated. By preparing a series
the interstices, is a well-known practice in pharmacy. of bismuth subnitrate suspensions containing increasing con-
To select suitable wetting agents that possess a well- centrations of monobasic potassium phosphate, Haines and
developed ability to penetrate the powder mass, Hiestand7 Martin10 were able to show a correlation between apparent
used a narrow trough, several inches long and made of a zeta potential and sedimentation volume, caking, and floccu-
hydrophobic material, such as Teflon, or coated with paraffin lation. The results are summarized in Figure 17–3 and are
wax. At one end of the trough is placed the powder and at explained in the following manner.
the other end the solution of the wetting agent. The rate of The addition of monobasic potassium phosphate to the
penetration of the latter into the powder can then be observed suspended bismuth subnitrate particles causes the positive
directly. zeta potential to decrease owing to the adsorption of the neg-
atively charged phosphate anion. With the continued addi-
tion of the electrolyte, the zeta potential eventually falls to
zero and then increases in the negative direction, as shown in
Controlled Flocculation Figure 17–3. Microscopic examination of the various suspen-
Assuming that the powder is properly wetted and dispersed, sions shows that at a certain positive zeta potential, maximum
we can now consider the various means by which controlled flocculation occurs and will persist until the zeta potential has
flocculation can be produced so as to prevent formation of become sufficiently negative for deflocculation to occur once
a compact sediment that is difficult to redisperse. The topic, again. The onset of flocculation coincides with the maxi-
described in detail by Hiestand,7 is conveniently discussed in mum sedimentation volume determined. F remains reason-
terms of the materials used to produce flocculation in suspen- ably constant while flocculation persists, and only when the
sions, namely electrolytes, surfactants, and polymers. zeta potential becomes sufficiently negative to effect repep-
Electrolytes act as flocculating agents by reducing the elec- tization does the sedimentation volume start to fall. Finally,
tric barrier between the particles, as evidenced by a decrease the absence of caking in the suspensions correlates with the
in the zeta potential and the formation of a bridge between maximum sedimentation volume, which, as stated previously,
P1: Trim: 8.375in × 10.875in
K E Y C O N C E P T WHAT IS A POLYMER?
Polymers are long-chain, high–molecular-weight compounds on the particle surface, with the remaining parts projecting out
containing active groups spaced along their length. These agents into the dispersion medium. Bridging between these latter por-
act as flocculating agents because part of the chain is adsorbed tions leads to the formation of flocs.
reflects the amount of flocculation. At less than maximum gelatin-coated particles being partially flocculated in sus-
values of F, caking becomes apparent. pension, presumably because the high negative charge has
These workers10 also demonstrated a similar correlation been replaced by a smaller, albeit positive, charge. Positively
when aluminum chloride was added to a suspension of sul- charged liposomes have been used as flocculating agents to
famerazine in water. In this system, the initial zeta poten- prevent caking of negatively charged particles. Liposomes
tial of the sulfamerazine particles is negative and is pro- are vesicles of phospholipids having no toxicity and that can
gressively reduced by adsorption of the trivalent aluminum be prepared in various particle sizes.15 They are adsorbed on
cation. When sufficient electrolyte is added, the zeta poten- the negatively charged particles.
tial reaches zero and then increases in a positive direction.
Colloidal and coarse dispersed particles can possess surface
charges that depend on the pH of the system. An important
Flocculation in Structured Vehicles
property of the pH-dependent dispersions is the zero point Although the controlled flocculation approach is capable
of charge, that is, the pH at which the net surface charge of fulfilling the desired physical chemical requisites of a
is zero. The desired surface charge can be achieved through pharmaceutical suspension, the product can look unsightly
adjusting the pH by the addition of HCl or NaOH to pro- if F, the sedimentation volume, is not close or equal to 1.
duce a positive, zero, or negative surface charge. The negative Consequently, in practice, a suspending agent is frequently
zeta potential of nitrofurantoin decreases considerably when added to retard sedimentation of the flocs. Such agents as
the pH values of the suspension are charged from basic to carboxymethylcellulose, Carbopol 934, Veegum, tragacanth,
acidic.11 and bentonite have been employed, either alone or in combi-
Surfactants, both ionic and nonionic, have been used to nation.
bring about flocculation of suspended particles. The concen- This can lead to incompatibilities, depending on the ini-
tration necessary to achieve this effect would appear to be tial particle charge and the charge carried by the flocculat-
critical because these compounds can also act as wetting and ing agent and the suspending agent. For example, suppose
deflocculating agents to achieve dispersion. we prepare a dispersion of positively charged particles that
Felmeister and others12 studied the influence of a xan- is then flocculated by the addition of the correct concentra-
than gum (an anionic heteropolysaccharide) on the floccu- tion of an anionic electrolyte such as monobasic potassium
lation characteristics of sulfaguanidine, bismuth subcarbon- phosphate. We can improve the physical stability of this sys-
ate, and other drugs in suspension. Addition of xanthan gum tem by adding a minimal amount of one of the hydrocolloids
resulted in increased sedimentation volume, presumably by just mentioned. No physical incompatibility will be observed
a polymer-bridging phenomenon. Hiestand13 reviewed the because the majority of hydrophilic colloids are themselves
control of floc structure in coarse suspensions by the addi- negatively charged and are thus compatible with anionic floc-
tion of polymeric materials. culating agents. If, however, we flocculate a suspension of
Hydrophilic polymers also act as protective colloids, and negatively charged particles with a cationic electrolyte (alu-
particles coated in this manner are less prone to cake than minum chloride), the subsequent addition of a hydrocolloid
are uncoated particles. These polymers exhibit pseudoplas- may result in an incompatible product, as evidenced by the
tic flow in solution, and this property serves to promote formation of an unsightly stringy mass that has little or no
physical stability within the suspension. Gelatin, a polyelec- suspending action and itself settles rapidly.
trolytic polymer, exhibits flocculation that depends on the Under these circumstances, it becomes necessary to use a
pH and ionic strength of the dispersion medium. Sodium sul- protective colloid to change the sign on the particle from neg-
fathiazole, precipitated from acid solution in the presence of ative to positive. This is achieved by the adsorption onto the
gelatin, was shown by Blythe14 to be free-flowing in the dry particle surface of a fatty acid amine (which has been checked
state and not to cake when suspended. Sulfathiazole normally to ensure its nontoxicity) or a material such as gelatin, which
carries a negative charge in aqueous vehicles. The coated is positively charged below its isoelectric point. We are then
material, precipitated from acid solution in the presence of able to use an anionic electrolyte to produce flocs that are
gelatin, however, was found to carry a positive charge. This compatible with the negatively charged suspending agent.
is due to gelatin being positively charged at the pH at which This approach can be used regardless of the charge on the
precipitation was carried out. It has been suggested8 that particle. The sequence of events is depicted in Figure 17–4,
the improved properties result from the positively charged which is self-explanatory.
P1: Trim: 8.375in × 10.875in
Fig. 17–4. The sequence of steps involved in the formation of a

Fig. 17–5. Rheologic flow curves of various suspending agents
stable suspension. (From A. Martin and J. Swarbrick, in Sprowls’
analyzed in a modified Stormer viscometer.
American Pharmacy, 6th Ed., Lippincott, Philadelphia, 1966, p. 206.
With permission.)
(Vanderbilt Co.), and a combination of bentonite and sodium

Rheologic Considerations carboxymethylcellulose. The hysteresis loop of bentonite is
quite marked. Veegum also shows considerable thixotropy,
The principles of rheology can be applied to a study of the fol-
both when tested by inverting a vessel containing the dis-
lowing factors: the viscosity of a suspension as it affects the
persion and when analyzed in a rotational viscometer. When
settling of dispersed particles, the change in flow properties
bentonite and carboxymethylcellulose dispersions are mixed,
of the suspension when the container is shaken and when the
the resulting curve shows both pseudoplastic and thixotropic
product is poured from the bottle, and the spreading qualities
characteristics. Such a combination should produce an
of the lotion when it is applied to an affected area. Rheo-
excellent suspending medium.
logic considerations are also important in the manufacture of
suspensions.
The only shear that occurs in a suspension in storage is due Preparation of Suspensions
to a settling of the suspended particles; this force is negligible
and may be disregarded. When the container is shaken and the The factors entering into the preparation and stabilization of
product is poured from the bottle, however, a high shearing suspensions involve certain principles of interest to physi-
rate is manifested. As suggested by Mervine and Chase,16 the cal pharmacy and are briefly discussed here. The physical
ideal suspending agent should have a high viscosity at negli-
gible shear, that is, during shelf storage; and it should have a
low viscosity at high shearing rates, that is, it should be free-
flowing during agitation, pouring, and spreading. As seen in
Figure 17–5, pseudoplastic substances such as tragacanth,
sodium alginate, and sodium carboxymethylcellulose show
these desirable qualities. The Newtonian liquid glycerin is
included in the graph for comparison. Its viscosity is suitable
for suspending particles but is too high to pour easily and to
spread on the skin. Furthermore, glycerin shows the undesir-
able property of tackiness (stickiness) and is too hygroscopic
to use in undiluted form. The curves in Figure 17–5 were
obtained by use of the modified Stormer viscometer.
A suspending agent that is thixotropic as well as pseu-
doplastic should prove to be useful because it forms a Fig. 17–6. Flow curves for 5% suspending agents in water, show-
gel on standing and becomes fluid when disturbed. Figure ing thixotropy. The curves were obtained with the Ferranti–Shirley
17–6 shows the consistency curves for bentonite, Veegum cone–plate viscometer.
P1: Trim: 8.375in × 10.875in
principles involved in the dispersion of solids by different sion is heated, the energy of repulsion between the particles
types of equipment were discussed by Oldshue.17 can be reduced owing to dehydration of the polyoxyethylene
A suspension is prepared on the small scale by grinding groups of the surfactant. The attractive energy is increased
or levigating the insoluble material in the mortar to a smooth and the particles flocculate.19 Zapata et al.20 studied the mech-
paste with a vehicle containing the dispersion stabilizer and anism of freeze–thaw instability in aluminum hydrocarbonate
gradually adding the remainder of the liquid phase in which and magnesium hydroxide gels as model suspensions because
any soluble drugs may be dissolved. The slurry is transferred of their well-known sensitivity to temperature changes. Dur-
to a graduate, the mortar is rinsed with successive portions of ing the freezing process, particles can overcome the repulsive
the vehicle, and the dispersion is finally brought to the final barrier caused by ice formation, which forces the particles
volume. close enough to experience the strong attractive forces present
On a large scale, dispersion of solids in liquids is in the primary minimum and form aggregates according to
accomplished by the use of ball, pebble, and colloid mills. the DLVO theory. When the ice melts, the particles remain as
Dough mixers, pony mixers, and similar apparatus are also aggregates unless work is applied to overcome the primary
employed. Only the colloid mill is described here; a discus- energy peak. Aggregate size was found to be inversely related
sion of the other mills can be found in the book by Fischer.18a to the freezing rate. The higher the freezing rate, the smaller
Dry grinding in ball mills is treated by Fischer,18a Berry and is the size of ice crystals formed. These small crystals do not
Kamack,18b and Prasher.18c result in the aggregation of as many suspension particles as
The colloid mill is based on the principle of a high- do large ice crystals.
velocity, cone-shaped rotor that is centered with respect to In addition to particle aggregation, particle growth is also
a stator at a small adjustable clearance. The suspension is fed a destabilizing process resulting from temperature fluctua-
to the rotor by gravity through a hopper, sheared between the tions or Ostwald ripening during storage. Fluctuations of
rotor and the stator, and forced out below the stator, where it temperature can change the particle size distribution and
may be recycled or drawn off. polymorphic form of a drug, altering the absorption rate and
The efficiency of the mill is based on the clearance between drug bioavailability.21 Particle growth is particularly impor-
the disks, the peripheral velocity of the rotor, and the non- tant when the solubility of the drug is strongly dependent on
Newtonian viscosity of the suspension. The mill breaks down the temperature. Thus, when temperature is raised, crystals of
the large aggregates and flocs so that they can be dispersed drug may dissolve and form supersaturated solutions, which
throughout the liquid vehicle and then protected by the dis- favor crystal growth. This can be prevented by the addition of
persion stabilizer. The shearing action that leads to disaggre- polymers or surfactants. Simonelli et al.3 studied the inhibi-
gation occurs at the surfaces of the rotating and stationary tion of sulfathiazole crystal growth by polyvinylpyrrolidone.
disks and between the particles themselves in a concentrated These authors suggested that the polymer forms a noncon-
suspension. If the yield value is too great, the material fails to densed netlike film over the sulfathiazole crystal, allowing
flow; if the viscosity is low, a loss in effectiveness of shearing the crystal to grow out only through the openings of the net.
action occurs. Therefore, the yield value should be low, and The growth is thus controlled by the pore size of the polymer
the plastic or apparent viscosity of the material should be at a network at the crystal surface. The smaller the pore size, the
maximum consistent with the optimum rate of flow through higher is the supersaturation of the solution required for the
the mill. If the material is highly viscous or if the plates are crystals to grow. This can be shown using the Kelvin equation
adjusted to a clearance that is too narrow, the temperature rises as applied to a particle suspended in a saturated solution3 :
rapidly, and cooling water must be circulated around the stator
to dissipate the heat that is produced. Dilatant materials—for c 2γ M
ln = (17–8)
example, deflocculated suspensions containing 50% or more co NkTρR
of solids—are particularly troublesome. They flow freely into
the mill but set up a high shearing rate and produce overheat- where c is the solubility of a small particle of radius R in
ing and stalling of the motor. Beginning any milling process an aqueous vehicle and co is the solubility of a very large
with the plates set at a wide clearance minimizes this danger. crystalline particle; γ is the interfacial tension of the crystal,
If this technique fails, however, the material must be milled in ρ is the density of the crystal, and M is the molecular weight
another type of equipment or the paste must be diluted with of the solute. N is Avogadro’s number, k is the Boltzmann
a vehicle until dilatancy is eliminated. constant, and N × k = 8.314 × 107 ergs−1 mole−1 . The
ratio c/co defines the supersaturation ratio that a large crystal
requires in the aqueous solution saturated with respect to the
Physical Stability of Suspensions small particle. According to equation (17–8), as the radius
Raising the temperature often leads to flocculation of ster- of curvature of a protruding crystal decreases, the protrusion
ically stabilized suspensions, that is, suspensions stabilized will require a correspondingly larger supersaturation ratio
by nonionic surfactants. Repulsion due to steric interactions before it can grow. The radius of curvature of a protrusion
depends on the nature, thickness, and completeness of the must equal that of the pore of the polymer on the crystal
surfactant-adsorbed layers on the particles. When the suspen- surface.
P1: Trim: 8.375in × 10.875in
EXAMPLE 17–4
Supersaturation Ratio
Assume that the interfacial tension of a particle of drug in an aque-
ous vehicle is 100 ergs/cm2 , its molecular weight is 200 g/mole, and
the temperature of the solution is 30◦ C or 303 K. (a) Compute the
supersaturation ratio, c/co , that is required for the crystal to grow.
The radius, R, of the particle is 5 μm, or 5 × 10−4 cm, and its density
is 1.3 g/cm3 . (b) Compute the supersaturation ratio when the parti-
cle is covered by a polymer and the pore radius, R, of the polymer
at the crystal surface is 6 × 10−7 cm.
Using the Kelvin equation, we obtain
(a)
c 2 × 100 × 200
ln = = 0.0024
co 8.314 × 107 × 1.3 × 303 × 5 × 10−4
(b)
c 2 × 100 × 200
ln = = 2.036
co 8.314 × 107 × 1.3 × 303 × 6 × 10−7
c/co = antiln(2.036) = 7.66
Notice that c/co in part (a) represents slight oversaturation,
whereas in (b) the supersaturation concentration must be 7.6 times
larger than the solubility of the drug molecule for the crystalline
particle to grow. In other words, the addition of a polymer greatly
increases the point at which supersaturation occurs and makes it
more difficult for the drug crystal to grow.
Ziller and Rupprecht22 designed a control unit to mon-

itor crystal growth and studied the inhibition of growth by
poly (vinylpyrrolidone) (PVP) in acetaminophen suspen-
sions. According to these workers, some of the segments of
the polymer PVP attach to the free spaces on the drug crystal
Fig. 17–7. Dissolution and crystallization of a drug in the presence
lattice and the polymer is surrounded by a hydration shell of a polymer adsorbed on the drug crystal. (From H. K. Ziller and
(Fig. 17–7). The adsorbed segments of the polymer inhibit H. Rupprecht, Drug Dev. Ind. Pharm. 14, 2341, 1988. With permission.)
crystal growth of acetaminophen because they form a bar-
rier that impedes the approach of the drug molecules from
the solution to the crystal surface. High–molecular-weight tive charge and is strongly adsorbed at the particle surface.
polymers of PVP are more effective than low–molecular- The positive end of the preservative molecule adsorbs on the
weight polymers because the adsorption of the polymer on negatively charged surface of the zinc oxide particles, form-
the crystal surface becomes more irreversible as the chain ing a layer with the hydrocarbon chains oriented outward
length increases. toward the dispersion medium. A second layer of preserva-
The stability of suspensions may also decrease owing tive adsorbs at this monolayer, with the positively charged
to interaction with excipients dissolved in the dispersion groups now directed toward the dispersion medium. Thus,
medium. Zatz and Lue19 studied the flocculation by sorbitol the physical stability of the suspension may be enhanced
in sulfamerazine suspensions containing nonionic surfactants owing to the repulsion of like-charged particles. However, the
as wetting agents. The flocculation by sorbitol depends on strong adsorption of the preservative on the zinc oxide parti-
the cloud point of the surfactant. Thus, the lower the cloud cles reduces the biologically active free fraction of preserva-
point, the less sorbitol was needed to induce flocculation. tive in the dispersion medium, and the microbiologic activity
The fact that the cloud point can be lowered by preservatives is diminished.
such as methylparaben shows that the choice of additives
may change the resistance to caking of a suspension con-
taining nonionic surfactants. Zatz and Lue19 suggested that EMULSIONS
the cloud point can be used to estimate the critical floccu-
lation concentration of sorbitol. Lucks et al.23 studied the An emulsion is a thermodynamically unstable system consist-
adsorption of preservatives such as cetylpyridinium chloride ing of at least two immiscible liquid phases, one of which is
on zinc oxide particles in suspension. Increasing amounts dispersed as globules (the dispersed phase) in the other liquid
of this preservative led to charge reversal of the suspension. phase (the continuous phase), stabilized by the presence of an
Cetylpyridinium chloride, a cationic surfactant, has a posi- emulsifying agent. The various types of emulsifying agents
P1: Trim: 8.375in × 10.875in
are discussed later in this section. Either the dispersed phase compounds, such as some vitamins, are absorbed more com-
or the continuous phase may range in consistency from that pletely when emulsified than when administered orally as
of a mobile liquid to a semisolid. Thus, emulsified systems an oily solution. The use of intravenous emulsions has been
range from lotions of relatively low viscosity to ointments and studied as a means of maintaining debilitated patients who
creams, which are semisolid in nature. The particle diameter are unable to assimilate materials administered orally. Tarr
of the dispersed phase generally extends from about 0.1 to et al.24 prepared emulsions of taxol, a compound with antim-
10 μm, although particle diameters as small as 0.01 μm and itotic properties, for intravenous administration as an alterna-
as large as 100 μm are not uncommon in some preparations. tive method to the use of cosolvents in taxol administration.
Davis and Hansrani25 studied the influence of droplet size
and emulsifying agents on the phagocytosis of lipid emul-
Emulsion Types sions. When the emulsion is administered intravenously, the
Invariably, one liquid phase in an emulsion is essentially polar droplets are normally rapidly taken up by the cells of the retic-
(e.g., aqueous), whereas the other is relatively nonpolar (e.g., uloendothelial system, in particular the fixed macrophages in
an oil). When the oil phase is dispersed as globules throughout the liver. The rate of clearance by the macrophages increases
an aqueous continuous phase, the system is referred to as an as the droplet size becomes larger or the surface charge, either
oil-in-water (o/w) emulsion. When the oil phase serves as the positive or negative, increases. Therefore, emulsion droplets
continuous phase, the emulsion is spoken of as a water-in-oil stabilized by a nonionic surfactant (zero surface charge) were
(w/o) product. Medicinal emulsions for oral administration cleared much more slowly than the droplets stabilized by neg-
are usually of the o/w type and require the use of an o/w atively charged phospholipids. Radiopaque emulsions have
emulsifying agent. These include synthetic nonionic surfac- found application as diagnostic agents in x-ray examinations.
tants, acacia, tragacanth, and gelatin. Not all emulsions that Emulsification is widely used in pharmaceutical and cos-
are consumed, however, belong to the o/w type. Certain foods metic products for external use. This is particularly so with
such as butter and some salad dressings are w/o emulsions. dermatologic and cosmetic lotions and creams because a
Externally applied emulsions may be o/w or w/o, the product that spreads easily and completely over the affected
former employing the following emulsifiers in addition to area is desired. Such products can now be formulated to be
the ones mentioned previously: sodium lauryl sulfate, tri- water washable and nonstaining and, as such, are obviously
ethanolamine stearate, monovalent soaps such as sodium more acceptable to the patient and the physician than some
oleate, and self-emulsifying glyceryl monostearate, that is, of the greasy products used a decade or more ago. Emulsi-
glyceryl monostearate mixed with a small amount of a mono- fication is used in aerosol products to produce foams. The
valent soap or an alkyl sulfate. Pharmaceutical w/o emulsions propellant that forms the dispersed liquid phase within the
are used almost exclusively for external application and may container vaporizes when the emulsion is discharged from
contain one or several of the following emulsifiers: polyva- the container. This results in the rapid formation of a foam.
lent soaps such as calcium palmitate, sorbitan esters (Spans),
cholesterol, and wool fat.
Several methods are commonly used to determine the type THEORIES OF EMULSIFICATION
of an emulsion. A small quantity of a water-soluble dye such
as methylene blue or brilliant blue FCF may be dusted on the There is no universal theory of emulsification because emul-
surface of the emulsion. If water is the external phase (i.e., sions can be prepared using several different types of emul-
if the emulsion is of the o/w type), the dye will dissolve and sifying agent, each of which depends for its action on a dif-
uniformly diffuse throughout the water. If the emulsion is of ferent principle to achieve a stable product. For a theory to
the w/o type, the particles of dye will lie in clumps on the be meaningful, it should be capable of explaining (a) the sta-
surface. A second method involves dilution of the emulsion bility of the product and (b) the type of emulsion formed.
with water. If the emulsion mixes freely with the water, it is of Let us consider what happens when two immiscible liquids
the o/w type. Another test uses a pair of electrodes connected are agitated together so that one of the liquids is dispersed as
to an external electric source and immersed in the emulsion. small droplets in the other. Except in the case of very dilute
If the external phase is water, a current will pass through the oil-in-water emulsions (oil hydrosols), which are somewhat
emulsion and can be made to deflect a voltmeter needle or stable, the liquids separate rapidly into two clearly defined
cause a light in the circuit to glow. If the oil is the continuous layers. Failure of two immiscible liquids to remain mixed
phase, the emulsion fails to carry the current. is explained by the fact that the cohesive force between the
molecules of each separate liquid is greater than the adhe-
sive force between the two liquids. The cohesive force of the
Pharmaceutical Applications individual phases is manifested as an interfacial energy or
An o/w emulsion is a convenient means of orally adminis- tension at the boundary between the liquids, as explained in
tering water-insoluble liquids, especially when the dispersed Chapter 15.
phase has an unpleasant taste. More significant in contem- When one liquid is broken into small particles, the interfa-
porary pharmacy is the observation that some oil-soluble cial area of the globules constitutes a surface that is enormous
P1: Trim: 8.375in × 10.875in
TABLE 17–1
SOME TYPICAL EMULSIFYING AGENTS∗
Type of Emulsion
Name Class Formed
Triethanolamine oleate Surface-active agent (anionic) o/w (HLB = 12)
N-cetyl N-ethyl morpholinium ethosulfate Surface-active agent (cationic) o/w (HLB = 25)
(Atlas G-263)
Sorbitan monooleate (Atlas Span 80) Surface-active agent (nonionic) w/o (HLB = 4.3)
Polyoxyethylene sorbitan monooleate Surface-active agent (nonionic) o/w (HLB = 15)
(Atlas Tween 80)
Acacia (salts of d-glucuronic acid) Hydrophilic colloid o/w
Gelatin (polypeptides and amino acids) Hydrophilic colloid o/w
Bentonite (hydrated aluminum silicate) Solid particle o/w (and w/o)
Veegum (magnesium aluminum silicate) Solid particle o/w
Carbon black Solid particle w/o
∗
Key: o/w = oil in water; w/o = water in oil; HLB = hydrophilic–lipophilic balance value.
compared with the surface area of the original liquid. If 1 cm3 Emulsifying agents can be divided into three groups, as fol-
of mineral oil is dispersed into globules having a volume– lows:
surface diameter, dvs of 0.01 μm (10−6 cm) in 1 cm3 of water
so as to form a fine emulsion, the surface area of the oil (a) Surface-active agents, which are adsorbed at oil–water
droplets becomes 600 m2 . The surface free energy associ- interfaces to form monomolecular films and reduce inter-
ated with this area is about 34 × 107 ergs, or 8 calories. The facial tension. These agents are discussed in detail in
total volume of the system, however, has not increased; it Chapter 15, dealing with interfacial phenomena.
remains at 2 cm3 . The calculations are made by use of equa- (b) Hydrophilic colloids (discussed in Chapter 16), which
tions (18–15) and (18–17) from which form a multimolecular film around the dispersed droplets
of oil in an o/w emulsion.26,27
6 (c) Finely divided solid particles, which are adsorbed at the
Sv =
dvs interface between two immiscible liquid phases and form
6 what amounts to a film of particles around the dispersed
Sv = = 6 × 106 cm2 = 600 m2
10−6 globules. The factor common to all three classes of emul-
sifying agent is the formation of a film, whether it be
The work input or surface free energy increase is given
monomolecular, multimolecular, or particulate.
by the equation W = γ ow × A, and the interfacial tension,
γ ow , between mineral oil and water is 57 dynes/cm (erg/cm2 ). On this basis, we can now discuss some of the more impor-
Thus, tant theories relating to the stability and type of emulsion
formed.
W = 57 ergs/cm2 × (6 × 106 cm2 )
Examples of typical emulsifying agents are given in Table
= 34 × 107 ergs = 34 joules 17–1.
and because 1 cal = 4.184 joules,

Monomolecular Adsorption
34 joules 4.184 = 8 calories
Surface-active agents, or amphiphiles, reduce interfacial ten-
In summary, if 1 cm3 of mineral oil is mixed with 1 cm3 sion because of their adsorption at the oil–water interface to
of water to produce fine particles (dvs = 0.01 μm), the total form monomolecular films. Because the surface free energy
surface is equivalent to an area slightly greater than that of increase, W, equals γ o/w × A and we must, of necessity,
a basketball court, or about 600 m2 . (In real emulsions, the retain a high surface area for the dispersed phase, any reduc-
particles are ordinarily about 10 to 100 times larger than this, tion in γ o/w , the interfacial tension, will reduce the surface
and the surface area is proportionately smaller.) The increase free energy and hence the tendency for coalescence. It is not
in energy, 8 calories, associated with this enormous surface unusual for a good emulsifying agent of this type to reduce
is sufficient to make the system thermodynamically unstable, the interfacial tension to 1 dyne/cm; we can therefore reduce
hence the droplets have a tendency to coalesce. the surface free energy of the system to approximately 1/60
To prevent coalescence or at least to reduce its rate to negli- of that calculated earlier.
gible proportions, it is necessary to introduce an emulsifying The reduction in surface free energy is of itself probably
agent that will form a film around the dispersed globules. not the main factor involved. Of more likely significance is
P1: Trim: 8.375in × 10.875in
Fig. 17–9. Schematic of oil droplets in an oil–water emulsion, show-

ing the orientation of a Tween and a Span molecule at the interface.
(From J. Boyd, C. Parkinson, and P. Sherman, J. Coll. Interface Sci.
41, 359, 1972. With permission.)
A hydrophilic Tween can be combined with a lipophilic

Span, varying the proportions so as to produce the desired
Fig. 17–8. Representations of combinations of emulsifying agents
o/w or w/o emulsion.29 Boyd et al.30 discussed the molecular
at the oil–water interface of an emulsion. (After J. H. Schulman and
E. G. Cockbain, Trans. Faraday Soc. 36, 651, 1940.)
association of Tween 40 and Span 80 in stabilizing emul-
sions. In Figure 17–9, the hydrocarbon portion of the Span
80 (sorbitan monooleate) molecule lies in the oil globule and
the sorbitan radical lies in the aqueous phase. The bulky sor-
the fact that the dispersed droplets are surrounded by a coher- bitan heads of the Span molecules prevent the hydrocarbon
ent monolayer that helps prevent coalescence between two tails from associating closely in the oil phase. When Tween
droplets as they approach one another. Ideally, such a film 40 (polyoxyethylene sorbitan monopalmitate) is added, it ori-
should be flexible so that it is capable of reforming rapidly ents at the interface such that part of its hydrocarbon tail is
if broken or disturbed. An additional effect promoting stain the oil phase and the remainder of the chain, together with
bility is the presence of a surface charge, which will cause the sorbitan ring and the polyoxyethylene chains, is located
repulsion between adjacent particles. in the water phase. It is observed that the hydrocarbon chain of
In practice, combinations of emulsifiers rather than single the Tween 40 molecule is situated in the oil globule between
agents are used most frequently today in the preparations of the Span 80 chains, and this orientation results in effective
emulsions. In 1940, Schulman and Cockbain28 first recog- van der Waals attraction. In this manner, the interfacial film is
nized the necessity of a predominantly hydrophilic emulsi- strengthened and the stability of the o/w emulsion is increased
fier in the aqueous phase and a hydrophobic agent in the oil against particle coalescence. The same principle of mixed
phase to form a complex film at the interface. Three mixtures emulsifying agents can be applied in the use of combinations
of emulsifying agents at the oil–water interface are depicted such as sodium stearate and cholesterol, sodium lauryl sulfate
in Figure 17–8. The combination of sodium cetyl sulfate and and glyceryl monostearate, and tragacanth and Span. Chun
cholesterol leads to a complex film (Fig. 17–8a) that pro- et al.31 determined the hydrophile–lipophile balance (HLB)
duces an excellent emulsion. Sodium cetyl sulfate and oleyl of some natural agents and further discussed the principle of
alcohol do not form a closely packed or condensed film (Fig. mixed emulsifiers.
17–8b), and, consequently, their combination results in a poor The type of emulsion that is produced, o/w or w/o, depends
emulsion. In Figure 17–8c, cetyl alcohol and sodium oleate primarily on the property of the emulsifying agent. This char-
produce a close-packed film, but complexation is negligible, acteristic is referred to as the hydrophile–lipophile balance,
and again a poor emulsion results. that is, the polar–nonpolar nature of the emulsifier. In fact,
P1: Trim: 8.375in × 10.875in
whether a surfactant is an emulsifier, wetting agent, deter- PHYSICAL STABILITY OF EMULSIONS

gent, or solubilizing agent can be predicted from a knowl-
edge of the HLB, as discussed in a previous chapter. In an Probably the most important consideration with respect to
emulsifying agent such as sodium stearate, C17 H35 COONa, pharmaceutical and cosmetic emulsions is the stability of the
the nonpolar hydrocarbon chain, C17 H35 , is the lipophilic finished product. The stability of a pharmaceutical emulsion
or “oil-loving” group; the carboxyl group, COONa, is the is characterized by the absence of coalescence of the internal
hydrophilic or “water-loving” portion. The balance of the phase, absence of creaming, and maintenance of elegance
hydrophilic and lipophilic properties of an emulsifier (or com- with respect to appearance, odor, color, and other physical
bination of emulsifiers) determines whether an o/w or w/o properties. Some workers define instability of an emulsion
emulsion will result. In general, o/w emulsions are formed only in terms of agglomeration of the internal phase and
when the HLB of the emulsifier is within the range of about 9 its separation from the product. Creaming, resulting from
to 12, and w/o emulsions are formed when the range is about flocculation and concentration of the globules of the internal
3 to 6. An emulsifier with a high HLB, such as a blend of phase, sometimes is not considered as a mark of instability.
Tween 20 and Span 20, will form an o/w emulsion. On the An emulsion is a dynamic system, however, and floccula-
other hand, Span 60 alone, having an HLB of 4.7, tends to tion and resultant creaming represent potential steps toward
form a w/o emulsion. complete coalescence of the internal phase. Furthermore, in
It would appear, therefore, that the type of emulsion is a the case of pharmaceutical emulsions, creaming results in a
function of the relative solubility of the surfactant, the phase lack of uniformity of drug distribution and, unless the prepa-
in which it is more soluble being the continuous phase. This ration is thoroughly shaken before administration, leads to
is sometimes referred to as the rule of Bancroft, who observed variable dosage. Certainly, the visual appeal of an emulsion
this phenomenon in 1913. Thus, an emulsifying agent with is affected by creaming, and this is just as real a problem to the
a high HLB is preferentially soluble in water and results in pharmaceutical compounder as is separation of the internal
the formation of an o/w emulsion. The reverse situation is phase.
true with surfactants of low HLB, which tend to form w/o Another phenomenon important in the preparation and
emulsions. Beerbower, Nixon, and Hill32 suggested an expla- stabilization of emulsions is phase inversion, which can be
nation for emulsion type and stability and devised a general an aid or a detriment in emulsion technology. Phase inversion
scheme for emulsion formulation based on the Hildebrand involves the change of emulsion type from o/w to w/o or vice
and Hansen solubility parameters. versa. Should phase inversion occur following preparation, it
may logically be considered as an instance of instability.
Multimolecular Adsorption and Film Formation In the light of these considerations, the instability of phar-
maceutical emulsions may be classified as follows:
Hydrated lyophilic colloids have been used for many years as
emulsifying agents, although their use is declining because (a) Flocculation and creaming
of the large number of synthetic surfactants now available. (b) Coalescence and breaking
In a sense, they can be regarded as surface active because (c) Miscellaneous physical and chemical changes
they appear at the oil–water interface. They differ, however, (d) Phase inversion
from the synthetic surface-active agents in that (a) they do
not cause an appreciable lowering of interfacial tension and
(b) they form a multi- rather than a monomolecular film at the Creaming and Stokes’s Law
interface. Their action as emulsifying agents is due mainly to
the latter effect because the films thus formed are strong and Those factors that find importance in the creaming of an emul-
resist coalescence. An auxiliary effect promoting stability sion are related by Stokes’s law, equation (17–2). The limita-
is the significant increase in the viscosity of the dispersion tions of this equation to actual systems have been discussed
medium. Because the emulsifying agents that form multilayer previously for suspensions, and these apply equally to emul-
films around the droplets are invariably hydrophilic, they tend sified systems.
to promote the formation of o/w emulsions. Analysis of the equation shows that if the dispersed phase
is less dense than the continuous phase, which is generally the
case in o/w emulsions, the velocity of sedimentation becomes
Solid-Particle Adsorption negative, that is, an upward creaming results. If the internal
Finely divided solid particles that are wetted to some degree phase is heavier than the external phase, the globules settle,
by both oil and water can act as emulsifying agents. This a phenomenon customarily noted in w/o emulsions in which
results from their being concentrated at the interface, where the internal aqueous phase is denser than the continuous oil
they produce a particulate film around the dispersed droplets phase. This effect can be referred to as creaming in a down-
so as to prevent coalescence. Powders that are wetted pref- ward direction. The greater the difference between the density
erentially by water form o/w emulsions, whereas those more of the two phases, the larger the oil globules, and the less vis-
easily wetted by oil form w/o emulsions. cous the external phase, the greater is the rate of creaming.
P1: Trim: 8.375in × 10.875in
By increasing the force of gravity through centrifugation, the Coalescence and Breaking
rate of creaming can also be increased. The diameter of the
globules is seen to be a major factor in determining the rate of Creaming should be considered as separate from breaking
creaming. Doubling the diameter of the oil globules increases because creaming is a reversible process, whereas breaking
the creaming rate by a factor of 4. is irreversible. The cream floccules can be redispersed eas-
ily, and a uniform mixture is reconstituted from a creamed
EXAMPLE 17–5 emulsion by agitation because the oil globules are still sur-
Velocity of Creaming
rounded by a protective sheath of emulsifying agent. When
breaking occurs, simple mixing fails to resuspend the glob-
Consider an o/w emulsion containing mineral oil with a specific
gravity of 0.90 dispersed in an aqueous phase having a specific grav- ules in a stable emulsified form because the film surrounding
ity of 1.05. If the oil particles have an average diameter of 5 μm, or the particles has been destroyed and the oil tends to coalesce.
5 × 10−4 cm, the external phase has a viscosity of 0.5 poise (0.5 dyne Considerable work has been devoted to the study of break-
sec/cm2 or 0.5 g/cm sec), and the gravity constant is 981 cm/sec2 , ing instability. The effects of certain factors on breaking are
what is the velocity of creaming in cm/day?
summarized in the following paragraphs.
We have
King35 showed that reduction of particle size does not nec-
(5 × 10−4 )2 × (0.90 − 1.05) × 981 essarily lead to increased stability. Rather, he concluded that
v =
18 × 0.5 an optimum degree of dispersion for each particular system
= −4.1 × 10−6 cm/sec exists for maximum stability. As in the case of solid particles,
and because a 24-hr day contains 86,400 sec, the rate of upward
if the dispersion is nonuniform, the small particles wedge
creaming, −v, is between larger ones, permitting stronger cohesion so that the
internal phase can coalesce easily. Accordingly, a moderately
−υ = 4.1 × 10−6 cm/sec × 86,400 sec/day = 0.35 cm/day
coarse dispersion of uniform-sized particles should have the
best stability. Viscosity alone does not produce stable emul-
The factors in Stokes’s equation can be altered to reduce sions; however, viscous emulsions may be more stable than
the rate of creaming in an emulsion. The viscosity of the mobile ones by virtue of the retardation of flocculation and
external phase can be increased without exceeding the lim- coalescence. Viscous or “tacky” emulsifiers seem to facilitate
its of acceptable consistency by adding a viscosity improver shearing of the globules as the emulsion is being prepared in
or thickening agent such as methylcellulose, tragacanth, or the mortar, but this bears little or no relationship to stability.
sodium alginate. The particle size of the globules can be Knoechel and Wurster36 showed that viscosity plays only a
reduced by homogenization; this, in fact, is the basis for the minor role in the gross stability of o/w emulsions. Probably
stability against creaming of homogenized milk. If the aver- an optimum rather than a high viscosity is needed to promote
age particle size of the emulsion in the example just given is stability.
reduced to 1 μm, or one fifth of the original value, the rate The phase–volume ratio of an emulsion has a secondary
of creaming is reduced to 0.014 cm/day or about 5 cm/year. influence on the stability of the product. This term refers to
Actually, when the particles are reduced to a diameter below the relative volumes of water and oil in the emulsion. As
2 to 5 μm, Brownian motion at room temperature exerts suf- shown in the section on powders, uniform spherical particles
ficient influence so that the particles settle or cream more in loose packing have a porosity of 48% of the total bulk
slowly than predicted by Stokes’s law. volume. The volume occupied by the spheres must then be
Little consideration has been given to the adjustment 52%.
of densities of the two phases in an effort to reduce the If the spheres are arranged in closest packing, theoreti-
rate of creaming. Theoretically, adjusting the external and cally they cannot exceed 74% of the total volume regardless
internal phase densities to the same value should elimi- of their size. Although these values do not consider the distor-
nate the tendency to cream. This condition is seldom real- tions of size and shape and the possibility of small particles
ized, however, because temperature changes alter the den- lying between larger spheres, they do have some significance
sities. Some research workers have increased the density of with respect to real emulsions. Ostwald and Kolloid37 showed
the oil phase by the addition of oil-soluble substances such that if one attempts to incorporate more than about 74% of
as α-bromonaphthalene, bromoform, and carbon tetrachlo- oil in an o/w emulsion, the oil globules often coalesce and
ride, which, however, cannot be used in medicinal products. the emulsion breaks. This value, known as the critical point,
Mullins and Becker33 added a food grade of a brominated oil is defined as the concentration of the internal phase above
to adjust the densities in pharmaceutical emulsions. which the emulsifying agent cannot produce a stable emul-
Equation (17–2) gives the rate of creaming of a single sion of the desired type. In some stable emulsions, the value
droplet of the emulsion, whereas one is frequently interested may be higher than 74% owing to the irregular shape and
in the rate of creaming at the center of gravity of the mass size of the globules. Generally speaking, however, a phase–
of the disperse phase. Greenwald34 developed an equation volume ratio of 50:50 (which approximates loose packing)
for the mass creaming rate, to which the interested reader is results in about the most stable emulsion. This fact was dis-
referred for details. covered empirically by pharmacists many years ago, and most
P1: Trim: 8.375in × 10.875in
Fig. 17–10. Parental emulsion droplets in the presence of the negatively charged emulsifier lecithin and
stabilized by electrostatic repulsion by calcium ions. The emulsion may be flocculated and destabilized
by the bridging effect of heparin, a negatively charged polyelectrolyte, which overcomes the stabilizing
electrostatic repulsion of the Ca2+ ions. (From O. L. Johnson, C. Washington, S. S. Davis, and K. Schaupp,
Int. J. Pharm. 53, 237, 1989. With permission.)
medicinal emulsions are prepared with a volume ratio of the surface of droplets stabilized with lecithin to form 1:2
50 parts of oil to 50 parts of water. ion–lipid complexes. This causes a charge reversal on the
Emulsions can be stabilized by electrostatic repulsion droplets, leading to positively charged particles. The droplets
between the droplets, that is, by increasing their zeta potential. are then flocculated by a bridging of the negatively charged
Magdassi and Siman-Tov38 used lecithin to stabilize perfluo- heparin molecules across the positively charged particles, as
rocarbon emulsions, which appear to be a good blood substi- depicted in Figure 17–10.
tute. Lecithin is a mixture of phospholipids having a negative When the oil particles, which usually carry a negative
charge at physiologic pH. The stabilizing effect is due to the charge, are surrounded in an o/w emulsion by a film of emul-
adsorption of lecithin at the droplet surface, which creates sifier, particularly a nonionic agent, the electrokinetic effects
a negative charge and consequently electrostatic repulsion. are probably less significant than they are in suspensions in
Lecithin produces very stable emulsions of triglyceride acids maintaining the stability of the system. The effect of elec-
in water for intravenous administration. However, the stabil- trolytes in these systems has been studied by Schott and
ity of these emulsions may be poor because in clinical prac- Royce.41 Probably the most important factors in the stabiliza-
tice they are mixed with electrolytes, amino acids, and other tion of an emulsion are the physical properties of the emul-
compounds for total parenteral nutrition. The addition of sifier film at the interface. To be effective, an emulsifier film
positively charged species such as sodium and calcium ions must be both tough and elastic and should form rapidly dur-
or cationic amino acids—the charge on the latter depending ing emulsification. Serrallach et al.42 measured the strength of
on the pH—reduces the zeta potential and may cause floc- the film at the interface. They found that a good emulsifying
culation. Johnson et al.39 studied the effect of heparin and agent or emulsifier combination brings about a preliminary
various electrolytes, frequently used clinically, on the sta- lowering of the interfacial tension to produce small uniform
bility of parenteral emulsions. Heparin, an anticoagulant, is globules and forms rapidly to protect the globules from reag-
a negatively charged polyelectrolyte that causes rapid floc- gregation during manufacture. The film then slowly increases
culation in emulsions containing calcium and lecithin. The in strength over a period of days or weeks.
critical flocculation concentration occurs at a specific zeta
potential. The value of this zeta potential can be determined
by plotting the flocculation rate against the surface poten-
Evaluation of Stability
tial and extrapolating to zero flocculation rate.40 Johnson According to King and Mukherjee,43 the only precise method
et al.39 explained the destabilizing effect of heparin as fol- for determining stability involves a size–frequency analysis
lows. Divalent electrolytes such as calcium bind strongly to of the emulsion from time to time as the product ages. For
P1: Trim: 8.375in × 10.875in
this method unsatisfactory because the globules can undergo

considerable coalescence before the separation becomes vis-
ible. These workers conducted particle-size analyses with a
Coulter centrifugal photosedimentometer. Mean volume
diameters were obtained, and these were converted to number
of globules per milliliter. King and Mukherjee43 determined
the specific interfacial area, that is, the area of interface per
gram of emulsified oil, of each emulsion at successive times.
They chose the reciprocal of the decrease of specific interfa-
cial area with time as a measure of the stability of an emulsion.
Other methods used to determine the stability of emulsions
are based on accelerating the separation process, which nor-
mally takes place under storage conditions. These methods
employ freezing, thaw–freeze cycles, and centrifugation.
Merrill46 introduced the centrifuge method for evaluating
Fig. 17–11. Particle-size distribution of an emulsion. Such curves
ordinarily are skewed to the right as shown in the figure, and the the stability of emulsions. Garrett, Vold, and others47 used
mode diameter, that is, the highest point on the curve or the most the ultracentrifuge as an analytic technique in emulsion tech-
frequent value, is seen to occur at the lower end of the scale of nology. Coulter counting, turbidimetric analysis, and tem-
diameters. The arithmetic mean diameter, dav , will be found some- perature tests have also been used in an effort to evaluate
what to the right of the mode in a right-skewed distribution, and the new emulsifying agents and determine the stability of phar-
mean volume–surface diameter, dvs , is to the right of the arithmetic maceutical emulsions. Garti et al.48 developed a method for
mean. evaluating the stability of oil–water viscous emulsions (oint-
ments and cosmetic creams) containing nonionic surfactants.
rapidly breaking emulsions, macroscopic observation of sep- The method is based on electric conductivity changes during
arated internal phase is adequate, although the separation is nondestructive short heating–cooling–heating cycles. Con-
difficult to read with any degree of accuracy. In the micro- ductivity curves are plotted during the temperature cycling.
scopic method, the particle diameters are measured, and a A stability index is defined as /h, where h is the change
size–frequency distribution of particles ranging from 0.0 to in the conductivity between 35◦ C and 45◦ C and is the
0.9 μm, 1.0 to 1.9 μm, 2.0 to 2.9 μm, and so on, is made conductivity interval within the two heating curves at 35◦ C,
as shown in Figure 17–11. The particle size or diameter of as shown in Figure 17–12. The stability index indicates the
the globules in micrometers is plotted on the horizontal axis relative change in conductivity between two cycles. The
against the frequency or number of globules in each size range smaller the conductivity, the greater is the stability of
on the vertical axis. Finkle et al.44 were probably the first the emulsion. The method was applied in a series of emulsions
workers to use this method to determine the stability of emul- at different HLBs, emulsifier concentrations, and oil-phase
sions. Since that time, many similar studies have been made.
Schott and Royce45 showed that the experimental problems
involved in microscopic size determinations are Brownian
motion, creaming, and field flow. Brownian motion affects the
smallest droplets, causing them to move in and out of focus
so that they are not consistently counted. Velocity of cream-
ing is proportional to the square of the droplet diameter, and
creaming focuses attention on the largest droplets because
they move faster toward the cover glass than do smaller ones.
Field flow is the motion of the entire volume of emulsion in
the field due to the pressure exerted by the immersion objec-
tive on the cover glass, evaporation of the continuous phase,
or convection currents resulting from heating by the light
source. These workers45 described an improved microscopic
technique that overcomes these experimental problems and
gives a more accurate measure of the droplet size.
An initial frequency distribution analysis on an emulsion is
not an adequate test of stability because stability is not related
to initial particle size. Instead, one should perhaps consider
the coalescence of the dispersed globules of an aging emul- Fig. 17–12. A conductivity versus temperature plot involving suc-
sion or the separation of the internal phase from the emul- cessively (a) heating, (b) cooling, and (c) heating. (From N. Garti and
sion over a period of time. Boyd et al.,30 however, deemed S. Magdassi, Drug Dev. Ind. Pharm. 8, 475, 1982. With permission.)
P1: Trim: 8.375in × 10.875in
concentrations. The authors reviewed earlier work on elec- concentration remaining in the aqueous phase. The phase–
tric conductivity of emulsions as related to stability. volume ratio of the emulsion is significant in this regard. In
addition, the preservative must be in an un-ionized state to
Phase Inversion penetrate the bacterial membrane. Therefore, the activity of
weak acid preservatives decreases as the pH of the aqueous
When controlled properly during the preparation of an emul-
phase rises. Finally, the preservative molecules must not be
sion, phase inversion often results in a finer product, but when
“bound” to other components of the emulsion, because the
it gets out of hand during manufacturing or is brought about
complexes are ineffective as preservatives. Only the concen-
by other factors after the emulsion is formed, it can cause
tration of free, or unbound, preservative is effective. These
considerable trouble.
points have been discussed in some detail in earlier sections.
An o/w emulsion stabilized with sodium stearate can be
In addition to partitioning, ionization, and binding, the effi-
inverted to the w/o type by adding calcium chloride to form
cacy of a particular preservative is also influenced by emul-
calcium stearate. Inversion can also be produced by alter-
sion type, nutritive value of the product, degree of aeration,
ations in phase-volume ratio. In the manufacture of an emul-
and type of container used. These factors are discussed by
sion, one can mix an o/w emulsifier with oil and then add a
Wedderburn.49
small amount of water. Because the volume of the water is
small compared with that of the oil, the water is dispersed
by agitation in the oil even though the emulsifier preferen-
tially forms an oil-in-water system. As more water is slowly
RHEOLOGIC PROPERTIES OF EMULSIONS
added, the inversion point is gradually reached and the water
Emulsified products may undergo a wide variety of shear
and emulsifier envelope the oil as small globules to form the
stresses during either preparation or use. In many of these
desired o/w emulsion. This procedure is sometimes used in
processes, the flow properties of the product will be vital for
the preparation of commercial emulsions, and it is the princi-
the proper performance of the emulsion under the conditions
ple of the continental method used in compounding practice.
of use or preparation. Thus, spreadability of dermatologic and
The preparation of emulsions is discussed in books on general
cosmetic products must be controlled to achieve a satisfac-
pharmacy and on compounding and dispensing.
tory preparation. The flow of a parenteral emulsion through
a hypodermic needle, the removal of an emulsion from a bot-
PRESERVATION OF EMULSIONS tle or a tube, and the behavior of an emulsion in the various
milling operations employed in the large-scale manufacture
Although it is not always necessary to achieve sterile con- of these products all indicate the need for correct flow char-
ditions in an emulsion, even if the product is for topical or acteristics. Accordingly, it is important for the pharmacist
oral use, certain undesirable changes in the properties of the to appreciate how formulation can influence the rheologic
emulsion can be brought about by the growth of microor- properties of emulsions.
ganisms. These include physical separation of the phases, The fundamentals of rheology are discussed in Chapter 19.
discoloration, gas and odor formation, and changes in rhe- Most emulsions, except dilute ones, exhibit non-Newtonian
ologic properties.49 Emulsions for parenteral use obviously flow, which complicates interpretation of data and quantita-
must be sterile. tive comparisons among different systems and formulations.
The propagation of microorganisms in emulsified prod- In a comprehensive review, Sherman50 discussed the princi-
ucts is supported by one or more of the components present pal factors that influence the flow properties of emulsions.
in the formulation. Thus, bacteria have been shown to degrade The material of this section outlines some of the viscosity-
nonionic and anionic emulsifying agents, glycerin, and veg- related properties of the dispersed phase, the continuous
etable gums present as thickeners, with a consequent deteri- phase, and the emulsifying agent. For a more complete dis-
oration of the emulsion. As a result, it is essential that emul- cussion of these and other factors that can modify the flow
sions be formulated to resist microbial attack by including properties of emulsions, the reader is referred to the original
an adequate concentration of preservative in the formula- article by Sherman50 and Sherman’s book.51
tion. Given that the preservative has inherent activity against The factors related to the dispersed phase include the
the type of contamination encountered, the main problem phase–volume ratio, the particle-size distribution, and the vis-
is obtaining an adequate concentration of preservative in cosity of the internal phase itself. Thus, when volume concen-
the product. Some of the factors that must be considered to tration of the dispersed phase is low (less than 0.05), the sys-
achieve this end are presented here. tem is Newtonian. As the volume concentration is increased,
Emulsions are heterogeneous systems in which partition- the system becomes more resistant to flow and exhibits pseu-
ing of the preservative will occur between the oil and water doplastic flow characteristics. At sufficiently high concentra-
phases. In the main, bacteria grow in the aqueous phase of tions, plastic flow occurs. When the volume concentration
emulsified systems, with the result that a preservative that is approaches 0.74, inversion may occur, with a marked change
partitioned strongly in favor of the oil phase may be virtually in viscosity; reduction in mean particle size increases the
useless at normal concentration levels because of the low viscosity; and the wider the particle size distribution, the
P1: Trim: 8.375in × 10.875in
lower is the viscosity when compared with a system hav-

ing a similar mean particle size but a narrower particle-size
distribution.
The major property of the continuous phase that affects
the flow properties of an emulsion is not, surprisingly, its own
viscosity. The effect of the viscosity of the continuous phase F
may be greater, however, than that predicted by determining
Mi
r
te
ne
the bulk viscosity of the continuous phase alone. There are
Wa
ral
indications that the viscosity of a thin liquid film, of say 100 to
oil
200 Å, is several times the viscosity of the bulk liquid. Higher
viscosities may therefore exist in concentrated emulsions G
when the thickness of the continuous phase between adja-
cent droplets approaches these dimensions. Sherman pointed
out that the reduction in viscosity with increasing shear may
be due in part to a decrease in the viscosity of the continu- F
ous phase as the distance of separation between globules is
increased. 9:1 Brij 96-Propylene glycol
Another component that may influence the viscosity of
an emulsion is the emulsifying agent. The type of agent will Fig. 17–13. A ternary-phase diagram of water, mineral oil, and a
affect particle flocculation and interparticle attractions, and mixture of surfactants showing the boundary of the microemulsion
these in turn will modify flow. In addition, for any one system, region. The zones within the microemulsion region are labeled F for
fluid and G for gel. (From N. J. Kate and L. V. Allen, Jr., Int. J. Pharm.
the greater the concentration of emulsifying agent, the higher
57, 87, 1989. With permission.)
will be the viscosity of the product. The physical properties of
the film and its electric properties are also significant factors. and enlarge the microemulsion droplet size without affecting
stability. With ionic surfactants at normal temperatures, one
expects o/w microemulsions to be formed when the phase vol-
MICROEMULSIONS ume ratio favors water, analogous to the rule for macroemul-
sions.
The term microemulsion may be a misnomer because The microemulsion region is usually characterized by
microemulsions consist of large or “swollen” micelles con- constructing ternary-phase diagrams, as shown in Figure
taining the internal phase, much like that found in a solu- 17–13, the axes representing water, mineral oil, and a mix-
bilized solution. Unlike the common macroemulsions, they ture of surfactant and cosurfactant at different ratios.53 The
appear as clear, transparent solutions, but unlike micellar phase diagrams allow one to determine the ratios oil:water:
solubilized systems, microemulsions may not be thermo- surfactant–cosurfactant at the boundary of the microemul-
dynamically stable. They appear to represent a state inter- sion region. The microemulsion appears by visual obser-
mediate between thermodynamically stable solubilized solu- vation as an isotropic, optically clear liquid system. Kale
tions and ordinary emulsions, which are relatively unstable. and Allen53 studied water-in-oil microemulsions consisting
Microemulsions contain droplets of oil in a water phase (o/w) of the system Brij 96-cosurfactant–mineral oil–water. Brij
or droplets of water in oil (w/o) with diameters of about 10 96 [polyoxyethylene(10) oleyl ether] is a nonionic surfactant
to 200 nm, and the volume fraction of the dispersed phase commonly used in the preparation of macro- and microemul-
varies from 0.2 to 0.8. sions. The cosurfactants studied were ethylene glycol, propy-
As often recommended in the formation of ordinary emul- lene glycol, and glycerin. Figure 17–13 shows the phase dia-
sions or macroemulsions, an emulsifying adjunct or cosurfac- gram for the system upon varying the ratio Brij 96:propylene
tant is used in the preparation of microemulsions. An anionic glycol. Within the microemulsion region, zones of different
surfactant, sodium lauryl sulfate or potassium oleate, can viscosity, labeled as fluid (F) or gel (G), can be observed. The
be dispersed in an organic liquid such as benzene, a small microemulsion region becomes smaller as the cosurfactant
measured amount of water is added, and the microemulsion concentration increases. According to the researchers, the
is formed by the gradual addition of pentanol, a lipophilic transition from fluid microemulsion to gel-like microemul-
cosurfactant, to form a clear solution at 30◦ C. The addition sion may be due to the change in the nature and shape of
of pentanol temporarily reduces the surface tension to approx- the internal oil phase. Thus, at low water content the inter-
imately zero, allowing spontaneous emulsification. The sur- nal phase consists of spherical structures, whereas at higher
factant and cosurfactant molecules form an adsorbed film on water concentration the interfacial film expands to form gel-
the microemulsion particles to prevent coalescence. like cylindrical and laminar structures. As the water content
Shinoda and Kunieda52 showed that by choosing a sur- is further increased, aqueous continuous systems of low vis-
factant and cosurfactant that have similar HLB values, one cosity with internal phases of spherical structures (droplets)
can increase the solubilization of an organic liquid in water are again formed.
P1: Trim: 8.375in × 10.875in
The droplet average molecular weight of a microemulsion aminobenzoic acid (PABA) from water-in-oil microemul-
can be measured by light-scattering techniques. Because the sions and macroemulsions. The delivery of these compounds
internal phase is not usually very dilute, the droplets inter- from microemulsions was faster and showed deeper pene-
act with one another, resulting in a decrease in the turbid- tration into the skin than delivery from the macroemulsions.
ity. Thus, the effective diameter obtained is smaller than the The authors reviewed a number of studies on the delivery
actual droplet diameter. The latter can be obtained from a of drugs from the microemulsions. These reports, including
plot of the effective diameter (obtained at various dilutions of several patents, dealt with the incorporation of fluorocarbons
the microemulsion) against the concentration of the internal as blood substitutes and for the topical delivery of antihy-
phase. Extrapolation to zero concentration gives the actual pertensive and anti-inflammatory drugs. Microemulsions are
diameter.53 Attwood and Ktistis54 showed that the extrap- used in cosmetic science,58 foods, and dry cleaning and wax-
olation procedure often cannot be applied because many polishing products.59
microemulsions exhibit phase separation on dilution. They
described a procedure for overcoming these difficulties and
obtaining true particle diameter using light scattering. SEMISOLIDS
Microemulsions have been studied as drug delivery sys-
tems. They can be used to increase the bioavailability of Gels
drugs poorly soluble in water by incorporation of the drug A gel is a solid or a semisolid system of at least two con-
into the internal phase. Halbert et al.55 studied the incorpo- stituents, consisting of a condensed mass enclosing and inter-
ration of both etoposide and a methotrexate diester deriva- penetrated by a liquid. When the coherent matrix is rich in liq-
tive in water-in-oil microemulsions as potential carriers for uid, the product is often called a jelly. Examples are ephedrine
cancer chemotherapy. Etoposide was rapidly lost from the sulfate jelly and the common table jellies. When the liquid is
microemulsion particles, whereas 60% of the methotrex- removed and only the framework remains, the gel is known
ate diester remained incorporated in the internal phase of as a xerogel. Examples are gelatin sheets, tragacanth ribbons,
the microemulsion. The methotrexate diester microemulsions and acacia tears.
showed an in vitro cytotoxic effect against mouse leukemia Hydrogels retain significant amounts of water but remain
cells. Microemulsions have also been considered as topical water-insoluble and, because of these properties, are often used
drug delivery systems. Osborne et al.56 studied the transder- in topical drug design. The diffusion rate of a drug depends on
mal permeation of water from water-in-oil microemulsions the physical structure of the polymer network and its chemical
formed from water, octanol, and dioctyl sodium sulfosucci- nature. If the gel is highly hydrated, diffusion occurs through
nate, the latter functioning as the surfactant. These kinds of the pores. In gels of lower hydration, the drug dissolves in
microemulsions can be used to incorporate polar drugs in the polymer and is transported between the chains.60 Cross-
the aqueous internal phase. The skin used in the experiments linking increases the hydrophobicity of a gel and diminishes
was fully hydrated so as to maximize the water permeability. the diffusion rate of the drug. The fractional release, F, of a
The delivery of the internal phase was found to be highly drug from a gel at time t can be expressed in general as
dependent on the microemulsion water content: The diffu-
Mt
sion of water from the internal phase increased tenfold as F= = kt n (17–9)
the water amount in the microemulsion increased from 15% M0
to 58% by weight. Linn et al.57 compared delivery through where Mt is the amount released at time t, M0 is the initial
hairless mouse skin of cetyl alcohol and octyl dimethyl para- amount of drug, k is the rate constant, and n is a constant
K E Y C O N C E P T CLASSIFICATION OF GELS
Gels can be classified as two-phase or single-phase systems. tragacanth and carboxymethylcellulose. These gels are consid-
The gel mass may consist of floccules of small particles rather ered to be one-phase systems because no definite boundaries
than large molecules, as found in aluminum hydroxide gel, ben- exist between the dispersed macromolecules and the liquid.
tonite magma, and magnesia magma, and the gel structure in Gels can be classified as inorganic and organic. Most inor-
these two-phase systems is not always stable (Fig. 17–14a and ganic gels can be characterized as two-phase systems, whereas
b). Such gels may be thixotropic, forming semisolids on standing organic gels belong to the single-phase class because the
and becoming liquids on agitation. condensed matrix is dissolved in the liquid medium to form a
On the other hand, a gel may consist of macromolecules exist- homogeneous gelatinous mixture. Gels may contain water, and
ing as twisted, matted strands (Fig. 17–14c). The units are often these are called hydrogels, or they may contain an organic
bound together by stronger types of van der Waals forces so as liquid, in which case they are called organogels. Gelatin gel
to form crystalline and amorphous regions throughout the entire belongs to the former class, whereas petrolatum falls in the latter
system, as shown in Figure 17–14d. Examples of such gels are group.
P1: Trim: 8.375in × 10.875in
Fig. 17–14. Representations of gel structures. (a) Flocculated par-

ticles in a two-phase gel structure. (b) Network of elongated par-
ticles or rods forming a gel structure. (c) Matted fibers as found
in soap gels. (d) Crystalline and amorphous regions in a gel of Fig. 17–15. Swelling isotherms of gelatin at (•) 25◦ C and (◦) at 20◦ C.
carboxymethylcellulose. (From H. R. Kruyt, Colloid Science, Vol. II, Swelling is measured as the increase in weight of gelatin strips in
Elsevier, New York, 1949.) buffer solution at various times. The points a and b are discussed in
the text. (From C. M. Ofner III and H. Schott, J. Pharm. Sci. 75, 790,
1986. With permission.)
called the diffusional exponent. When n = 0, tn = 1 and the
release F is of zero order; if n = 0.5, Fick’s law holds and the
release is represented by a square root equation. Values of n tion with the liberation of oil or water from ointment bases
greater than 0.5 indicate anomalous diffusion due generally usually results from a deficient gel structure rather than from
to the swelling of the system in the solvent before the release the contraction involved in syneresis.
takes place.61 Morimoto et al.62 prepared a polyvinyl alcohol The opposite of syneresis is the taking up of liquid by a
hydrogel for rectal administration that has a porous, tridimen- gel with an increase in volume. This phenomenon is known
sional network structure with high water content. The release as swelling. Gels may also take up a certain amount of liquid
of indomethacin from the gel followed Fickian diffusion over without a measurable increase in volume, and this is called
a period of 10 hr. imbibition. Only those liquids that solvate a gel can bring
about swelling. The swelling of protein gels is influenced by
EXAMPLE 17–6 pH and the presence of electrolytes.
Diffusional Component Ofner and Schott63 studied the kinetics of swelling of
The release fraction, F, of indomethacin is 0.49 at t = 240 min. gelatin by measuring the increase in weight of short rect-
Compute the diffusional exponent, n, knowing that k = 3.155% angular strips of gelatin films after immersion in buffer solu-
min−n . tions as a function of time, t. A plot of the weight, W, in
Because the rate constant k is expressed as percentage, the frac- grams of aqueous buffer absorbed per gram of dry gelatin
tional release, F, is also expressed in percentage units in equation
(17–9), that is, 49%. Taking the ln on both sides of equation (17–9), against t in hours gives the swelling isotherms (Fig. 17–15).
we obtain The horizontal portions of the two isotherms correspond to
equilibrium swelling. To obtain a linear expression, t/W is
ln F = ln k + n ln t plotted against t (the plot is not shown here) according to the
ln F − ln k ln 49 − ln 3.155 equation
n= =
ln t ln 240
3.892 − 1.149 t
n=
5.481
= 0.5 = A + Bt (17–10)
W
Therefore, with the exponent of t equal to 0.5, equation (17–9)
becomes F = kt1/2 , which is a Fickian diffusion. Rearranging and differentiating equation (17–10), we obtain
dW A
Syneresis and Swelling = (17–11)
dt (A + Bt)2
When a gel stands for some time, it often shrinks naturally,
and some of its liquid is pressed out. This phenomenon, As t → 0, equation (17–11) gives the initial swelling rate,
known as syneresis, is thought to be due to the continued dW/dt = 1/A, which is the reciprocal of the intercept of
coarsening of the matrix or fibrous structure of the gel with equation (17–10). The reciprocal of the slope, 1/B = W∞ ,
a consequent squeezing-out effect. Syneresis is observed in is the equilibrium swelling, that is, the theoretical maximum
table jellies and gelatin desserts. The “bleeding” in connec- uptake of buffer solution at t∞ .
P1: Trim: 8.375in × 10.875in
EXAMPLE 17–7 property is important because diffusion of drugs in hydrogels

Initial Swelling Rate depends on the water content in the hydrogel. Kou et al.65
The increase in weight of 330 mg for a 15% gelatin sample 0.27 mm used phenylpropanolamine as a model compound to study
thick was measured in 0.15 M ammonium acetate buffer at 25◦ C. its diffusion in copolymers of 2-hydroxyethyl methacrylate
∗
The t/W values at several time periods are as follows: and methacrylic acid cross-linked with tetraethylene glycol
dimethacrylate. The drug diffusivity, D, in the gel matrix is
t (hr) 0.5 1 1.5 2 3 4 related to the matrix hydration by the relation
hr
t/W 0.147 0.200 0.252 0.305 0.410 0.515
g(buffer)/g(gelatin) 1
ln D = ln Do − K f −1 (17–12)
H
Compute the initial swelling rate and the equilibrium swelling. where Do is the diffusivity of the solute in water and Kf is a
A regression of t/W against t gives constant characteristic of the system. The term H represents
t the matrix hydration and is defined as
= 0.0946 + 0.1051 t
W
Equilibrium swollen gel weight − Dry gel weight
The initial swelling rate, 1/A, is the reciprocal of the intercept, H=
Equilibrium swollen gel weight
1 1
= = 10.57 g(buffer solution)/hr g(gelatin)
A 0.0946 According to equation (17–12), a plot of ln D against 1/
The equilibrium swelling is (H − 1) should be linear with slope Kf and intercept ln Do .
1 1 g(buffer solution)
W∞ = = = 9.513 EXAMPLE 17–8
B 0.1051 g(gelatin)
Diffusion Coefficients
Compute the diffusion coefficients of phenylpropanolamine in a gel
Equation (17–10) represents a second-order process. for two gel hydrations, H = 0.4 and H = 0.9. The diffusion coefficient
When the constants A and B are used to backcalculate the of the solute in water is Do = 1.82 × 10−6 cm2 /sec, and Kf , the
swelling, W, at several times and are compared with the exper- constant of equation (17–12), is 2.354.
For H = 0.4,
imental data, the higher deviations are found in the region of
maximum curvature of the isotherms (Fig. 17–15). Ofner and 1
ln D = ln(1.82 × 10−6 ) − 2.354 − 1 = −16.748
Schott63 attributed the deviations to the partially crystalline 0.4
structure of gelatin. Thus, the first part of curve a in Figure D = 5.33 × 10−8 cm2 /sec
17–15 corresponds to the swelling of the amorphous region, For H = 0.9,
which is probably complete at times corresponding to max-
1
imum curvature, namely 6 to 10 hr at 20◦ C. The penetration ln D = ln(1.82 × 10−6 ) − 2.354 − 1 = −13.479
0.9
of the solvent into the crystalline region is slower and less
D = 1.4 × 10−6 cm2 /sec
extensive because this region is more tightly ordered and has
a higher density (part b of the curve in Fig. 17–15). The swelling (hydration) of the gel favors drug release because
it enhances the diffusivity of the drug, as shown in the example.
Gelatin is probably the most widely employed natural
polymer in pharmaceutical products; it is used in the prepara-
tion of soft and hard gelatin capsules, tablet granulations and
coatings, emulsions, and suppositories. Gelatin may inter- Classification of Pharmaceutical Semisolids
act with gelatin-encapsulated drugs or excipients by absorb- Semisolid preparations, with special reference to those used
ing significant amounts of them, and some compounds may as bases for jellies, ointments, and suppositories, can be clas-
change the dissolution rate of soft gelatin capsules. Ofner and sified as shown in Table 17–2. The arrangement is arbitrary
Schott64 studied the effect of six cationic, anionic, and non- and suffers from certain difficulties, as do all classifications.
ionic drugs or excipients on the initial swelling rate and equi- Some confusion of terminology has resulted in recent
librium swelling in gelatin. The cationic compounds reduced years, partly as a result of the rapid development of the
the equilibrium swelling, W∞ , substantially, whereas the non- newer types of bases. Terms such as “emulsion-type,” “water-
ionic and anionic compounds increased it. The researchers washable,” “water-soluble,” “water-absorbing,” “absorption
suggested that the cationic additives such as quaternary base,” “hydrophilic,” “greaseless,” and others have appeared
ammonium compounds may cause disintegration and dis- in the literature as well as on the labels of commercial bases
solution problems with both hard and soft gelatin capsules. where the meaning is obscure and sometimes misleading. The
Cross-linked hydrogels with ionizable side chains swell title “greaseless” has been applied both to water-dispersible
extensively in aqueous media. The swelling depends on the bases that contain no grease and to o/w bases because they
nature of the side groups and the pH of the medium. This feel greaseless to the touch and are easily removed from the
skin and clothing. The terms “cream” and “paste” are also
∗ The data are calculated from the slope and intercept given in Table III in often used ambiguously. Pectin paste is a jelly, whereas zinc
Ofner and Schott.64 oxide paste is a semisolid suspension. And what does the term
P1: Trim: 8.375in × 10.875in
TABLE 17–2
A CLASSIFICATION OF SEMISOLID BASES
Examples
I. Organogels
A. Hydrocarbon type Petrolatum, mineral oil–polyethylene gel∗
B. Animal and vegetable fats Lard, hydrogenated vegetable oils, Theobroma oil
C. Soap base greases Aluminum stearate, mineral oil gel
D. Hydrophilic organogels Carbowax bases, polyethylene glycol ointment
II. Hydrogels
A. Organic hydrogels Pectin paste, tragacanth jelly
B. Inorganic hydrogels Bentonite gel, colloidal magnesium aluminum silicate gels
III. Emulsion-type semisolids
A. Emulsifiable bases
1. Water-in-oil (absorption) Hydrophilic petrolatum, wool fat
2. Oil-in-water Anhydrous Tween base†
B. Emulsified bases
1. Water-in-oil Hydrous wool fat, rose water ointment
2. Oil-in-water Hydrophilic ointment, vanishing cream
∗
Plastibase (E. R. Squibb). J. Am. Pharm. Assoc. Sci. Ed. 45, 104, 1956.
†
White petrolatum, stearyl alcohol, glycerin, Tween 60 (Atlas-ICI).
“absorption base” mean? Does it imply that the base is read- able. They have the disadvantage of water loss by evapora-
ily absorbed into the skin, that drugs incorporated in such a tion and of possible mold and bacterial growth, thus requiring
base are easily released and absorbed percutaneously, or that preservation. Two classes of emulsion bases are discussed:
the base is capable of absorbing large quantities of water? emulsifiable and emulsified.
These few examples point out the difficulties that arise when
different titles are used for the same product or when different (a) Emulsifiable bases. We choose to call these bases emul-
definitions are given to the same term. sifiable because they initially contain no water but are
capable of taking it up to yield w/o and o/w emulsions.
Organogels The w/o types are commonly known as absorption bases
Petrolatum is a semisolid gel consisting of a liquid com- because of their capacity to absorb appreciable quantities
ponent together with a “protosubstance” and a crystalline of water or aqueous solutions without marked changes
waxy fraction. The crystalline fraction provides rigidity to in consistency.
the gel structure, whereas the protosubstance or gel former (b) Emulsified bases. Water-in-oil bases in which water is
stabilizes the system and thickens the gel. Polar organogels incorporated during manufacture are referred to in this
include the polyethylene glycols of high molecular weight book as emulsified w/o bases to differentiate them from
known as Carbowaxes (Union Carbide Corp., New York). The the emulsifiable w/o bases (absorption bases), which
Carbowaxes are soluble to about 75% in water and therefore contain no water. The emulsified oil-in-water bases are
are completely washable, although their gels look and feel formulated as is any emulsion with an aqueous phase,
like petrolatum. an oil phase, and an emulsifying agent. The components
of emulsified ointments, however, differ in some ways
Hydrogels from the ingredients of liquid emulsions.
Bases of this class include organic and inorganic ingre-
dients that are colloidally dispersible or soluble in water. The oil phase of the ointment may contain petrolatum,
Organic hydrogels include the natural and synthetic gums natural waxes, fatty acids or alcohols, solid esters, and sim-
such as tragacanth, pectin, sodium alginate, methylcellulose, ilar substances that increase the consistency of the base and
and sodium carboxymethylcellulose. Bentonite mucilage is provide certain desirable application properties.
an inorganic hydrogel that has been used as an ointment base
in about 10% to 25% concentration. Comparison of Emulsion Bases
The absorption bases have the advantage over oleaginous
Emulsion-Type Bases products in absorption of large amounts of aqueous solution.
Emulsion bases, as might be expected, have much greater Furthermore, they are compatible with most drugs and are sta-
affinity for water than do the oleaginous products. ble over long periods. When compared with o/w bases, the
The o/w bases have an advantage over the w/o bases in that w/o preparations are superior in that they do not lose water
the o/w products are easily removed from the skin and do not readily by evaporation because water is the internal phase.
stain clothing. These bases are sometimes called water wash- Although emulsified o/w or washable bases do have the
P1: Trim: 8.375in × 10.875in
undesirable property of drying out when not stored properly

and of losing some water during compounding operations,
they are more acceptable than the nonwashable absorption
bases because they are easily removed with water from the
skin and clothing.
Hydrophilic Properties of Semisolids

Petrolatum is hydrophilic to a limited degree, taking up about
10% to 15% by weight of water through simple incorporation.
The water-absorbing capacity of oleaginous and water-in-
oil bases can be expressed in terms of the water number, first
defined in 1935 by Casparis and Meyer66 as the maximum
quantity of water that is held (partly emulsified) by 100 g
of a base at 20◦ C. The test consists in adding increments
of water to the melted base and triturating until the mixture
has cooled. When no more water is absorbed, the product Fig. 17–16. Flow curves for hydrophilic petrolatum and hydrophilic
is placed in a refrigerator for several hours, removed, and petrolatum containing water. (After H. B. Kostenbauder and
allowed to come to room temperature. The material is then A. Martin, J. Am. Pharm. Assoc. Sci. Ed. 43, 401, 1954.)
rubbed on a slab until water no longer exudes, and, finally,
the amount of water remaining in the base is determined. mately the same relationship. The curves of Figure 17–18
Casparis and Meyer found the water number of petrolatum suggest strongly that it is the alternation of thixotropy
to be about 9 to 15; the value for wool fat is about 185. with temperature that differentiates the two bases. Because
thixotropy is a consequence of gel structure, Figure 17–18
Rheologic Properties of Semisolids shows that the waxy matrix of petrolatum is probably bro-
ken down considerably as the temperature is raised, whereas
Manufacturers of pharmaceutical ointments and cosmetic the resinous structure of Plastibase withstands temperature
creams have recognized the desirability of controlling the changes over the ranges ordinarily encountered in its use.
consistency of non-Newtonian materials. Based on data and curves such as these, the pharmacist
Probably the best instrument for determining the rheologic in the development laboratory can formulate ointments with
properties of pharmaceutical semisolids is some form of a more desirable consistency characteristics, the worker in the
rotational viscometer. The cone–plate viscometer is particu-
larly well adapted for the analysis of semisolid emulsions and
suspensions. The Stormer viscometer, consisting of a station-
ary cup and rotating bob, is also satisfactory for semisolids
when modified, as suggested by Kostenbauder and Martin.67
Consistency curves for the emulsifiable bases hydrophilic
petrolatum and hydrophilic petrolatum in which water has
been incorporated are shown in Figure 17–16. It will be
observed that the addition of water to hydrophilic petrolatum
has lowered the yield point (the intersection of the extrapo-
lated downcurve and the load axis) from 520 to 340 g. The
plastic viscosity (reciprocal of the slope of the downcurve)
and the thixotropy (area of the hysteresis loop) are increased
by the addition of water to hydrophilic petrolatum.
The effect of temperature on the consistency of an oint-
ment base can be analyzed by use of a properly designed
rotational viscometer. Figures 17–17 and 17–18 show the
changes of plastic viscosity and thixotropy, respectively, of
petrolatum and Plastibase as a function of temperature.68
The modified Stormer viscometer was used to obtain these
curves. As observed in Figure 17–17, both bases show about
the same temperature coefficient of plastic viscosity. These Fig. 17–17. The temperature coefficient of plastic viscosity of (•)
results account for the fact that the bases have about the Plastibase (E. R. Squibb and Sons, New Brunswick, NJ) and (◦)
same degree of “softness” when rubbed between the fingers. petrolatum. (From A. H. C. Chun, M. S. Thesis, Purdue University,
Curves of yield value versus temperature follow approxi- Purdue, Ind., June 1956.)
P1: Trim: 8.375in × 10.875in
EXAMPLE 17–9
Rigidity Index
The rigidity degradation of a 6% pharmaceutical-grade gelatin USP
was studied69 at 65◦ C. The rigidity index values at several times are
as follows:
t (hr) 10 20 30 40 50
1 −1
(g ) 0.0182 0.0197 0.0212 0.0227 0.0242
f
Compute the rigidity index, f0 , at time zero and the rate constant,
kf , at 65◦ C.
The regression of 1/f versus t gives the equation
1
= 1.5 × 10−4 t + 0.0167
f
At t = 0 we have intercept 1/f0 = 0.0167 g−1 ; f0 = 59.9 g. The
slope is kf = 1.5 × 10−4 g−1 hr−1 . Using the regression equation,
we can compute the rigidity index, f, at time t, say 60 hr:
1
= (1.5 × 10−4 × 60) + 0.0167 = 0.0257 g−1
f
1
f = = 38.9 g
0.0257
The force needed to depress the gelatin surface has decreased
Fig. 17–18. The temperature coefficient of thixotropy of Plastibase from its original value, f0 = 59.9 g. Therefore, gelatin lost rigidity
after heating for 60 hr.
(E. R. Squibb and Sons) and petrolatum. (After A. H. C. Chun, M. S.
Thesis, Purdue University, Purdue, Ind., June 1956.)
The effect of temperature on the rate constant, kf , can be
expressed using the Arrhenius equation,
production plant can better control the uniformity of the fin-
ished product, and the dermatologist and the patient can be kf = Ae−Ea /RT (17–15)
assured of a base that spreads evenly and smoothly in various Thus, a plot of ln kf against 1/T gives the Arrhenius con-
climates, yet adheres well to the affected area and is not tacky stant, A, and the energy of activation, Ea .
or difficult to remove. Fassihi and Parker70 measured the change in the rigid-
Rigidity and viscosity are two separate parameters used to ity index, f, of 15% to 40% gelatin gel, USP type B, before
characterize the mechanical properties of gels. Ling69 studied and after gamma irradiation (which is used to sterilize the
the effect of temperature on rigidity and viscosity of gelatin. gelatin). They found that the rigidity index diminished with
He used a rigidity index, f, which is defined as the force irradiation and that the kinetics of rigidity degradation is com-
required to depress the gelatin surface a fixed distance. To plex. For gels containing more than 20% gelatin, the rigidity
measure rigidity, a sample of gelatin solution or gel mass is index follows a sigmoidal curve at increasing radiation doses,
subjected to penetrative compression by a flat-ended cylindri- as shown in Figure 17–19. Gelatin is widely used in tablet
cal plunger that operates at a constant speed. In this method, manufacturing as a binder to convert fine powders into gran-
the strain rate (rate of deformation of the gel) is constant and ules. The loss of rigidity index reduced the binding proper-
independent of stress (force applied). Ling found that thermal ties of gelatin and decreased the hardness of lactose granules
degradation with respect to rigidity followed second-order prepared with irradiated gelatin. These workers suggested
kinetics, that doses of gamma radiation should be held to less than 2
megarad (Mrad) to obtain gelatins of acceptable quality for
−df/dt = kf f 2 (17–13)
pharmaceutical applications.
The integrated form of equation (17–13) is
Universe of Topical Medications
1 1
− = kf t (17–14) Katz71 devised a “universe of topical medications” (Fig.
f f0
17–20) by which one can consider the various topical medi-
where f is the rigidity index of the gelatin solution or gelatin cations such as pastes, absorption bases, emulsified products,
gel at time t, f0 is the rigidity index at time zero, kf is the rate lotions, and suspensions. The basic components of most der-
constant (g−1 hr−1 ), and t is the heating time in hours. The matologic preparations are powder, water, oil, and emulsifier.
quantities f0 and kf can be computed from the intercept and Beginning at A on the “universal wheel” of Figure 17–20,
the slope of equation (17–14) at a given temperature. one is confronted with the simple powder medication, used
P1: Trim: 8.375in × 10.875in
F to change the ointment into a w/o cream. At G, the base is

predominantly water, and an o/w emulsifier is used to form
the opposite type of emulsion, that is, an o/w cream. Still more
water and less oil converts the product into an o/w lotion at
H. At point I on the universal wheel, only water remains, both
oil and surfactant being eliminated, and this segment of the
wheel represents an aqueous liquid preparation, a soak, or a
compress.
Finally, at section J, the powder from A is incorporated,
and the aqueous product becomes a shake preparation, as
represented by calamine lotion. Accordingly, this ingenious
wheel classifies nearly all types of topical preparations from
solid pastes and ointments, through w/o and o/w emulsions, to
liquid applications and shake lotions. It serves as a convenient
way to discuss the various classes of dermatologic and toiletry
products that are prepared by the manufacturer or practicing
pharmacist and applied topically by the patient.
Fig. 17–19. Rigidity index of gelatin gel as a function of gamma irra-
diation at various concentrations (15%–40%) of the gel. (From A. R.
Fassihi and M. S. Parker, J. Pharm. Sci. 77, 876, 1988. With permis-
sion.)
DRUG KINETICS IN COARSE DISPERSE SYSTEMS
The kinetics of degradation of drugs in suspension72 can be
as a protective, drying agent and lubricant and as a carrier described as a pseudo–zero-order process (see Chapter 14),
for locally applied drugs. Passing counterclockwise around
the wheel, we arrive at the paste, B, which is a combina- M = M0 − k1 VCs t (17–16)
tion of powder from segment A and an oleaginous material where k1 is the first-order constant of the dissolved drug, V
such as mineral oil or petrolatum. An oleaginous ointment for is the volume of the suspension, and Cs is the solubility of
lubrication and emolliency and devoid of powder is shown in the drug. If the solubility is very low, the kinetics can be
segment C. described as found in the section on solid-state kinetics (see
The next section, D, is a waterless absorption base, consist- Chapter 14). For very viscous dispersed systems, the kinetics
ing of oil phase and w/o emulsifier and capable of absorbing of degradation can be partially controlled by the dissolution
aqueous solutions of drugs. At the next region of the wheel, rate as given by the Noyes–Whitney equation,
E, water begins to appear along with oil and emulsifier, and a
w/o emulsion results. The proportion of water is increased at dc/dt = KS(Cs − C) (17–17)
where Cs is the solubility of the drug, C is the concentration
of solute at time t, S is the surface area of the expanded solid,
and K is the dissolution rate constant. It is assumed that as a
molecule degrades in the liquid phase it is replaced by another
molecule dissolving. The overall decrease in concentration in
the liquid phase can be written as
dc/dt = −kC + KS(Cs − C) (17–18)
where −kC expresses the rate of disappearance at time t due
to degradation, and KS(Cs − C) is the rate of appearance of
the drug in the liquid phase due to dissolution of the particles.
The solution of this differential equation is
C = [Cs KS/(k1 + KS)]e−(k1 +SK)t (17–19)
At large t values, C becomes
C = Cs KS/(k1 + KS) (17–20)
and the amount of drug remaining in suspension at large
Fig. 17–20. Universe of topical medication. (From M. Katz, in E. J. values of t is
Ariens (Ed.), Drug Design, Academic Press, New York, 1973. With
permission.) M = M0 − [k1 SKCs V/(k1 + KS)]t (17–21)
P1: Trim: 8.375in × 10.875in
where M0 is the initial amount of drug in suspension. Equa-

tion (17–21) is an expression for a zero-order process, as
is equation (17–16), but the slopes of the two equations are
different. Because the dissolution rate constant, K, in equa-
tion (17–21) is proportional to the diffusion coefficient, D,
K is inversely proportional to the viscosity of the medium;
therefore, the more viscous the preparation, the greater is the
stability.
EXAMPLE 17–10
Particles and Decomposition
The first-order decomposition rate of a drug in aqueous solution is
5.78 × 10−4 sec−1 and the dissolution rate constant, K, is 3.35 ×
10−6 cm−2 sec−1 . What is the amount of drug remaining in 25 cm3
of a 5% w/v suspension after 3 days? Assume spherical particles of Fig. 17–21. The pH–log(kobs ) profile for degradation of fluocinolone
mean volume diameter, dvn , 2 × 10−4 cm. The density of the powder acetonide and triamcinolone acetonide at 50◦ C. Key: = experimen-
is 3 g/cm3 and the solubility of the drug is 2.8 × 10−4 g/cm3 . tally determined kobs (month−1 ) for fluocinolone acetonide cream;
The initial amount of drug is
= triamcinolone acetonide solution. The solid lines were obtained
5 M0 from the calculated values of kobs using equation (17–22). (From A.

= , M0 = 1.25 g/25 cm3 Kenley, M. O. Lee, L. Sukumar, and M. Powell, Pharm. Res. 4, 342,
100 25
1987. With permission.)
The number of particles, N, in 25 cm3 can be computed from equa-
tion (18–4):
6 6 profile over the pH range of 2 to 6, with a minimum rate near

N= = pH 4. This may indicate that the degradation in oil-in-water
π(dvn )3 ρ 3.1416 × (2 × 10−4 )3 × 3
creams is confined to an aqueous environment, the nonaque-
particles
= 7.96 × 1010 ous components of the cream having little influence.73
gram
Because ln k = ln A − Ea /RT, where A is the Arrhenius
The number of particles in 1.25 g is N = 7.96 × 1010 × 1.25 = 9.95 factor and Ea is the energy of activation, equation (17–22)
× 1010 particles. can be rewritten in terms of activation parameters, A and Ea ,
The total surface area is
for each of the catalytic coefficients, ko , kH , and kOH :
S = Nπd 2 = 9.95 × 1010 × 3.1416 × (2 × 10−4 )2
= 1.25 × 104 cm2 k = exp[ln Ao − (E ao /RT )]
+ exp[ln AH − (E aH /RT )][H+ ] (17–23)
From equation (17–21),
+ exp[ln AOH − (E aOH /RT )][OH− ]
5.78 × 10−4 × 1.25 × 104 × 3.35
× 10−6 × 2.8 × 10−4 × 25
M = 1.25 − Equation (17–23) allows one to compute the degradation
5.78 × 10−4 + (3.35 × 10−6 × 1.25 × 104 )
rate constant k at several temperatures and pH values.
× (2.6 × 105 sec)
= 1.25 − [(3.99 × 10−6 )(2.6 × 105 )] = 1.25 − 1.0374 = 0.213 g EXAMPLE 17–11
Degradation Rate Constant
The natural logarithm of the Arrhenius parameters for neutral-,
Kenley et al.73 studied the kinetics of degradation of flu- acid-, and base-catalyzed hydrolysis of fluocinolone acetonide in
ocinolone acetonide incorporated into an oil-in-water cream oil-in-water creams are ln Ao = 22.5, ln AH = 38.7, and ln AOH =
base. The degradation followed a pseudo–first-order constant 49.5. The corresponding energies of activation are EaO = 17,200,
at pH values from 2 to 6 and at several temperatures. The EaH = 22,200, and EaOH = 21,100 cal/mole. The H+ and OH−
concentrations in equation (17–23) are expressed, as usual, in moles
observed rate constants increased with increasing tempera- per liter, and the first-order rate constant, k, is expressed in this
ture, and acid catalysis at low pH values and basic catalysis example in month−1 . Compute the degradation rate constant, k, at
at pH above 4 were observed. The observed rate constant for 40◦ C and pH 4.
the degradation process can be written as From equation (17–23),
k = ko + kH [H+ ] + kOH [OH− ] (17–22) k = exp[22.5 − (17,200/1.9872 × 313)]

+ exp[38.7 − (22,200/1.9872 × 313)] × (1 × 10−4 )
Figure 17–21 compares the degradation of fluocinolone ace- + exp[49.5 − (21,100/1.9872 × 313)] × (1 × 10−10 )
tonide from oil-in-water creams with that of triamcinolone = (5.782 × 10−3 ) + (2.025 × 10−3 ) + (5.820 × 10−4 )
acetonide, a related steroid, in aqueous solution. From the fig- k = 8.39 × 10−3 month−1
ure, both creams and solution share a similar log(Rate)−pH
P1: Trim: 8.375in × 10.875in
Teagarden et al.74 determined the rate constant, k, for the Ong and Manoukian76 studied the delivery of lonapalene,
degradation of prostaglandin E1 (PGE1 ) in an oil-in-water a nonsteroidal antipsoriatic drug, from an ointment, vary-
emulsion. At acidic pH values, the degradation of PGE1 ing the initial concentration of drug and the volume frac-
showed large rate constants. This fact was attributed to the tion of the internal phase. In the study, lonapalene was com-
greater effective concentration of hydrogen ions at the oil– pletely solubilized in the ointment systems. Most of the drug
water interface, where PGE1 is mainly located at low pH was dissolved in the internal phase, consisting of propylene
values. carbonate–propylene glycol, but a fraction was also solubi-
lized in the external phase of a petrolatum base consisting
of glyceryl monostearate, white wax, and white petrolatum.
DRUG DIFFUSION IN COARSE DISPERSE SYSTEMS The data were treated by the approximation of Higuchi,77

De t
The release of drugs suspended in ointment bases can be Q = 2C0 (17–25)
calculated from the Higuchi equation: π
where Q is the amount of drug released per unit area of appli-
Q = [D(2A − Cs )Cs t]1/2 (17–24) cation, C0 is the initial concentration in the ointment, De is
where Q is the amount of drug released at time t per unit area the effective diffusion coefficient of the drug in the ointment,
of exposure, Cs is the solubility of the drug in mass units per and t is the time after application. For a small volume of the
cm3 in the ointment, and A is the total concentration, both internal phase,
dissolved and undissolved, of the drug. D is the diffusion
D1 KD2 − D1
coefficient of the drug in the ointment (cm2 /sec). De = 1 + 3 φ2 (17–26)
φ1 + Kφ2 KD2 + 2D1
Iga et al.75 studied the effect of ethyl myristate on the
release rate of 4-hexylresorcinol from a petrolatum base at where the subscripts 1 and 2 refer to the external and internal
pH 7.4 and temperature 37◦ C. They found that the release phases, respectively, and K is the partition coefficient between
rate was proportional to the square root of time, according the two phases. When D2 is much greater than D1 ,
to the Higuchi equation. Increasing concentrations of ethyl D1 (1 + 3φ2 )
myristate enhanced the release rate of the drug owing to the De = (17–27)
φ1 + K φ2
increase of drug solubility, Cs , in the ointment [see equation
(17–24)]. This behavior was attributed to formation of 1:1 and De , the effective diffusion coefficient, is obtained from the
1:2 complexes between hexylresorcinol and ethyl myristate. release studies [equation (17–25)], and D1 can be computed
from equation (17–27) if one knows the volume fraction of the
EXAMPLE 17–12 external and internal phases, φ 1 and φ 2 , respectively. The drug
Calculate Q is released according to two separate rates: an initial nonlinear
The solubility of hexylresorcinol in petrolatum base is 0.680 mg/cm3 . and a linear, diffusion-controlled rate (Fig. 17–22). The ini-
After addition of 10% ethyl myristate, the solubility, Cs , of the drug tial rates extending over a period of 30 min are higher than the
is 3.753 mg/cm3 . Compute the amount, Q, of drug released after diffusion-controlled rates owing to the larger transference of
10 hr. The diffusion coefficient, D, is 1.31 × 10−8 cm2 /sec and the drug directly to the skin from the surface globules. The high
initial concentration, A, is 15.748 mg/cm3 .
initial rates provide immediate availability of the drug for
We have
Q = {(1.31 × 10−8 cm2 / sec)[(2 × 15.748 mg/cm3 )
1
− 0.68 mg/cm3 )]} 2
1
× [0.68 mg/cm3 ×(10×3600) sec] 2 = 0.099 mg/cm3
After addition of 10% ethyl myristate, we find
Q = {(1.31 × 10−8 cm2 / sec) [(2 × 15.748 mg/cm3 )
1
− 3.753 mg/cm3 )]} 2
1
× [3.753 mg/cm3 ×(10×3600) sec] 2 = 0.222 mg/cm2
The release of a solubilized drug from emulsion-type

creams and ointments depends on the drug’s initial concen-
tration. It is also a function of the diffusion coefficient of the
drug in the external phase, the partition coefficient between
the internal and external phases, and the volume fraction of Fig. 17–22. Amount per unit area, Q, of lonapalene at time t from
the internal phase. If the drug is completely solubilized in a an emulsion-type ointment. Key: = 0.5%; = 1.0%; and = 2.0%
minimum amount of solvent, the release from the vehicle is drug. (From J. T. H. Ong and E. Manoukian, Pharm. Res. 5, 16, 1988.
faster than it is from a suspension-type vehicle. With permission.)
P1: Trim: 8.375in × 10.875in
absorption. In addition, the release of drug from the exter- enhanced by complexation of the drug with a hydrosolu-
nal phase contributes to the initial rates. Equation (17–25) ble derivative of β-cyclodextrin. The increase in solubility
is applicable only to the linear portion of the graph, where and wettability as well as the decrease in crystallinity due
the process becomes diffusion controlled (Fig. 17–22). to an inclusion-type complexation may be the cause of the
enhanced release. On the other hand, complexation of flur-
EXAMPLE 17–13 biprofen with methylated cyclodextrins, which are oil soluble
Amount Released and surface active, enhances the release from hydrophilic
Compute the amount of lonapalene released per cm2 after t = suppository bases. This is due to the decreased interac-
24 hr from a 0.5% w/v emulsified ointment. The internal phase tion between the drug complex and the hydrophilic base.81
of the ointment consists of the drug solubilized in a propylene
Coprecipitation of indomethacin with PVP also enhances the
carbonate–propylene glycol mixture and the external phase is a
white petrolatum–glyceryl monostearate–white wax mixture. The release from lipid suppository bases because it improves wet-
volume fraction of the internal phase, φ2 , is 0.028, the diffusion ting, which avoids the formation of a cake at the oil–aqueous
coefficient of the drug in the external phase, D1 , is 2.60 × 10−9 suppository interface.82
cm2 /sec, and the partition coefficient, K, between the internal and Nyqvist-Mayer et al.83 studied the delivery of a eutec-
external phases is 69.
tic mixture of lidocaine and prilocaine (two local anesthet-
From equation (17–27), the effective diffusion coefficient is
ics) from emulsions and gels. Lidocaine and prilocaine form
(2.60 × 10−9 cm2 /sec)[1 + (3 × 0.028)] eutectic mixtures at approximately a 1:1 ratio. The eutectic
De =
(1 − 0.028) + (69 × 0.028) mixture has a eutectic temperature of 18◦ C, meaning that
= 0.97 × 10−9 cm2 /sec it is a liquid above 18◦ C and can therefore be emulsified at
Note that the sum of the volume fractions of internal and of room temperature. The mechanism of release from this emul-
external phases is equal to 1; therefore, knowing the external vol- sion and transport through the skin is complex owing to the
ume fraction to be φ2 = 0.028, one simply has the internal volume presence of freely dissolved species, surfactant-solubilized
fraction, φ1 = 1 − 0.028. The initial concentration of drug is 0.5 g species, and emulsified species of the local anesthetic mix-
per 100 cm3 , that is, 5 mg/mL. From equation (17–25), the amount
ture. The passage of these materials across the skin mem-
of lonapalene released after 24 hr is
brane is depicted in Figure 17–23. The solute lost due to
(0.97 × 10−9 cm2 /sec)×(24×3600) sec transport across the membrane is replenished by dissolution
Q = 2 × (5 mg/cm3 )
3.1416 of droplets as long as a substantial number of droplets are
= 0.05 mg/cm2 present. Micelles of surfactant with a fraction of the solubi-
lized drug may act as carriers across the aqueous diffusion
The rate of release also depends on the solubility of the layer, diminishing the diffusion layer resistance. Droplets
drug as influenced by the type of emulsion. Rahman et al.78 from the bulk are also transported to the boundary layer and
studied the in vitro release and in vivo percutaneous absorp- supply solute, which diffuses through the membrane, thus
tion of naproxen from anhydrous ointments and oil-in-water decreasing the limiting effect of the aqueous layer to dif-
and water-in-oil creams. The results fitted equation (17–25), fusion of solute. Because the oil phase of this emulsion is
the largest release rates being obtained when the drug was formed by the eutectic mixture itself, there is no transport
incorporated into the water phase of the creams by using the of drug between the inert oil and water, as occurs in a con-
soluble sodium derivative of naproxen. After application of ventional emulsion and which would result in a decreased
the formulations to rabbit skin, the absorption of the drug fol- thermodynamic activity, a, or “escaping tendency.” The sys-
lowed first-order kinetics, showing a good correlation with tem actually resembles a suspension that theoretically has
the in vitro release. high thermodynamic activity owing to the saturation of the
Chiang et al.79 studied the permeation of minoxidil, an drug in the external phase. In a suspension, the dissolution
antialopecia (antibaldness) agent, through the skin from rate of the particles could be a limiting factor. In contrast,
anhydrous, oil-in-water, and water-in-oil ointments. The rate the fluid state of the eutectic mixture lidocaine–prilocaine
of permeation was higher from water-in-oil creams.
Drug release from fatty suppositories can be character-
ized by the presence of an interface between the molten
base and the surrounding liquid. The first step is drug dif-
fusion into the lipid–water interface, which is influenced
by the rheologic properties of the suppository. In a second
step, the drug dissolves at the interface and is then trans-
ported away from the interface.80 Because the dissolution
of poorly water-soluble drugs on the aqueous side of the
lipid–water interface is the rate-limiting step, the release is Fig. 17–23. Delivery of a eutectic mixture of lidocaine–prilocaine
increased by the formation of a water-soluble complex. Arima from an emulsion into a receptor compartment. (From A. A. Nyqvist-
et al.80 found that the release of ethyl 4-biphenyl acetate, an Mayer, A. F. Borodin, and S. G. Frank, J. Pharm. Sci. 75, 365, 1986.
anti-inflammatory drug, from a lipid suppository base was With permission.)
P1: Trim: 8.375in × 10.875in
For lidocaine, according to equation (17–29),

1 127 × 10−4 cm 200 × 10−4 cm
= +
P (2.6 × 10−7 cm2 /sec) × 9.1 8.96 × 10−6 cm2 /sec
= 7599.8 sec/cm
P = 1/7599.8 = 1.32 × 10−4 cm/sec
For prilocaine,
1 127 × 10−4 cm 200 × 10−4 cm
= −7
+
P (3 × 10 cm /sec) × 4.4
2 9.14 × 10−6 cm2 /sec
= 11809.2 sec/cm
P = 1/11809.2 = 8.47 × 10−5 cm/sec
The permeability of the mixture PT can be calculated from the
proportion of each component.83 Because the proportion of lidocaine
is 1 and that of prilocaine 1.3, the total amount is 1 + 1.3 = 2.3.
Therefore, the permeability of the mixture is
(1 × 1.32 × 10−4 ) + (1.3 × 8.47 × 10−5 )
PT =
2.3
= 1.05 × 10−4 cm/sec
The total amount released from the emulsion consists of an

initial steady-state portion, from which the release rate can
Fig. 17–24. Release of lidocaine–prilocaine from an emulsion () be computed. When the formulation is thickened with car-
and from a gel (). (From A. A. Nyqvist-Mayer, A. F. Borodin, and bomer 934P (carbopol), a gel results. The release rates from
S. G. Frank, J. Pharm. Sci. 75, 365, 1986. With permission.) the gel and the emulsion are compared in Figure 17–24. In
the gel, the release rate continuously decreases owing to the
formation of a depletion zone in the gel. The thickness of
may promote a higher dissolution rate. The total resistance,
the stagnant diffusion layer next to the membrane increases
RT , to the skin permeation of the free dissolved fraction of
to such a degree that the release process becomes vehicle
prilocaine is given by the sum of the resistances of the aque-
controlled. After 1 hr, the amount delivered is a function of
ous layer, Ra , and the resistance of the membrane, Rm :
the square root of time, and the apparent diffusion coeffi-
cient in the gel can be computed from the Higuchi equation
RT = Ra + Rm (17–28)
(17–24). The release process is both membrane layer and
or aqueous layer controlled for nongelled systems (emulsions).
For gelled systems the initial release is also membrane layer
RT =
1
=
hm
+
ha
(17–29) and aqueous layer controlled, but later, at t > 1 hr, the release
P Dm K Da becomes formulation or vehicle controlled, that is, the slow-
est or rate-determining step in the diffusion of the drug is
where D is the diffusion coefficient of the drug, ha is the passage through the vehicle.
thickness of the aqueous layer, hm is the thickness of the
membrane, and P is the permeability coefficient associated
with the membrane and the aqueous layer; K is the partition CHAPTER SUMMARY
coefficient between the membrane and the aqueous layer. The
subscripts a and m stand for aqueous layer and membrane, Particulate systems have been classified on the basis of size
respectively. Equation (17–29) is analogous to equation (11– into molecular dispersions, colloidal systems, and coarse dis-
30), except that the constant 2 in the denominator has been persions. This chapter attempts to provide the pharmacist
eliminated in this case because we consider only one aqueous with an insight into the role of physics and chemistry in the
layer (Fig. 17–24). research and development of the several classes of coarse
dispersions. The theory and technology of these important
EXAMPLE 17–14 pharmaceutical classes are based on interfacial and colloidal
Compute the total permeability, P, of a 1:1.3 ratio of lidocaine– principles, micromeritics, and rheology (Chapters 15, 16,
prilocaine in the form of a eutectic mixture. The thicknesses of the 18 and 19, respectively). Pharmaceutical suspensions were
aqueous and membrane layers are 200 and 127 μm, respectively. The introduced and the roles they play in the pharmaceutical sci-
diffusion coefficient and the partition coefficient of the drugs at
the membrane–aqueous layers are as follows: lidocaine, Da = 8.96 × ences were described. In addition, the desirable qualities of
10−6 cm2 /sec, Dm = 2.6 = 10−7 cm2 /sec, and K = 9.1; prilocaine, pharmaceutical suspensions and the factors that affect the
Da = 9.14 × 10−6 cm2 /sec, Dm = 3 × 10−7 cm2 /sec, and K = 4.4. stability of suspensions were also discussed. The concepts
P1: Trim: 8.375in × 10.875in
of flocculation, settling and sedimentation theory were intro- 30. J. Boyd, C. Parkinson, and P. Sherman, J. Coll. Interface Sci. 41, 359,
duced and the student was shown how to calculate sedimen- 1972.
31. A. H. C. Chun, R. S. Joslin, and A. Martin, Drug Cosmet. Ind. 82, 164,
tation rates. Two useful sedimentation parameters, sedimen- 1958.
tation volume and degree of flocculation were discussed. The 32. A. Beerbower and J. Nixon, Am. Chem. Soc. Div. Petroleum
student should be aware of the approaches commonly used Chem. Preprints 14(1), 62, 1969; A. Beerbower and M. W. Hill, in
in the preparation of physically stable suspensions. Phar- McCutcheon’s Detergents and Emulsifiers, MC Publishing Company,
Princeton, WI. 1971, p. 223.
maceutical emulsions and emulsifying agents were intro- 33. J. Mullins and C. H. Becker, J. Am. Pharm. Assoc. Sci. Ed. 45, 110,
duced and the main types of emulsions discussed. The student 1956.
should be able to classify pharmaceutical semisolids as well 34. H. L. Greenwald, J. Soc. Cosmet. Chem. 6, 164, 1955.
as understand thixotropic properties, syneresis, and swelling. 35. A. King, Trans. Faraday Soc. 37, 168, 1941.
36. E. L. Knoechel and D. E. Wurster, J. Am. Pharm. Assoc. Sci. Ed. 48, 1,
Finally, examples of coarse dispersions were given. 1959.
37. W. Ostwald, Kolloid Z. 6, 103, 1910; 7, 64, 1910.
Practice problems for this chapter can be found at 38. S. Magdassi and A. Siman-Tov, Int. J. Pharm. 59, 69, 1990.
thePoint.lww.com/Sinko6e. 39. O. L. Johnson, C. Washington, S. S. Davis, and K. Schaupp, Int. J.
Pharm. 53, 237, 1989.
40. C. Washington, A. Chawla, N. Christy, and S. S. Davis, Int. J. Pharm.
54, 191, 1989.
References 41. H. Schott and A. E. Royce, J. Pharm. Sci. 72, 1427, 1983.
42. J. A. Serrallach, G. Jones, and R. J. Owen, Ind. Eng. Chem. 25, 816,
1. K. J. Frederick, J. Pharm. Sci. 50, 531, 1961.
1933.
2. J. C. Samyn, J. Pharm. Sci. 50, 517, 1961.
43. A. King and L. N. Mukherjee, J. Soc. Chem. Ind. 58, 243T, 1939.
3. A. P. Simonelli, S. C. Mehta, and W. I. Higuchi, J. Pharm. Sci. 59, 633,
44. P. Finkle, H. D. Draper, and J. H. Hildebrand, J. Am. Chem. Soc. 45,
1970.
2780, 1923.
4. W. Schneider, S. Stavchansky, and A. Martin, Am. J. Pharm. Educ. 42,
45. H. Schott and A. E. Royce, J. Pharm. Sci. 72, 313, 1983.
280, 1978.
46. R. C. Merrill, Jr., Ind. Eng. Chem. Anal. Ed. 15, 743, 1943.
5. K. S. Alexander, J. Azizi, D. Dollimore, and V. Uppala, J. Pharm. Sci.
47. E. R. Garrett, J. Pharm. Sci. 51, 35, 1962; R. D. Vold and R. C.
79, 401, 1990.
Groot, J. Phys. Chem. 66, 1969, 1962; R. D. Vold and K. L. Mittal, J.
6. E. F. Burton, in A. E. Alexander (Ed.), Colloid Chemistry, Vol. I, Rein-
Pharm. Sci. 61, 869, 1972; S. J. Rehfeld, J. Coll. Interface Sci. 46, 448,
hold, New York, 1926, p. 165.
1974.
7. E. N. Hiestand, J. Pharm. Sci. 53, 1, 1964.
48. N. Garti, S. Magdassi, and A. Rubenstein, Drug Dev. Ind. Pharm. 8, 475,
8. A. Martin, J. Pharm. Sci. 50, 513, 1961; R. A. Nash, Drug Cosmet. Ind.
1982.
97, 843, 1965.
49. D. L. Wedderburn, in Advances in Pharmaceutical Sciences, Vol. 1,
9. H. Schott, L. C. Kwan, and S. Feldman, J. Pharm. Sci. 71, 1038, 1982.
Academic Press, London, 1964, p. 195.
10. B. A. Haines and A. Martin, J. Pharm. Sci. 50, 228, 753, 756, 1961.
50. P. Sherman, J. Pharm. Pharmacol. 16, 1, 1964.
11. A. Delgado, V. Gallardo, J. Salcedo, and F. Gonzalez-Caballero,
51. P. Sherman (Ed.), Rheology of Emulsions, Pergamon Press, Oxford,
J. Pharm. Sci. 79, 82, 1990.
1963.
12. A. Felmeister, G. M. Kuchtyak, S. Kozioi, and C. J. Felmeister, J. Pharm.
52. K. Shinoda and H. Kunieda, J. Coll. Interface Sci. 42, 381, 1973; K.
Sci. 62, 2027, 1973; J. S. Tempio and J. L. Zaps, J. Pharm. Sci. 69, 1209,
Shinoda and S. Friberg, Adv. Coll. Interface Sci. 44, 281, 1975.
1980; J. Pharm. Sci. 70, 554, 1981; J. L. Zaps et al., Int. J. Pharm. 9,
53. N. J. Kale and J. V. Allen, Jr., Int. J. Pharm. 57, 87, 1989.
315, 1981.
54. D. Attwood and G. Ktistis, Int. J. Pharm. 52, 165, 1989.
13. E. N. Hiestand, J. Pharm. Sci. 61, 269, 1972.
55. G. W. Halbert, J. F. B. Stuart, and A. T. Florence, Int. J. Pharm. 21, 219,
14. R. H. Blythe, U. S. Patent 2,369,711, 1945.
1984.
15. S.-L. Law, W.-Y. Lo, and G.-W. Teh, J. Pharm. Sci. 76, 545, 1987.
56. D. W. Osborne, A. J. I. Ward, and K. J. O’Neill, Drug Dev. Ind. Pharm.
16. C. K. Mervine and G. D. Chase, Presented at the American Pharm.
14, 1203, 1988.
Association Meeting, 1952.
57. E. E. Linn, R. C. Pohland, and T. K. Byrd, Drug Dev. Ind. Pharm. 16,
17. J. Y. Oldshue, J. Pharm. Sci. 50, 523, 1961.
899, 1990.
18. (a) E. K. Fischer, Colloidal Dispersions, Wiley, New York, 1950; (b) C.
58. H. L. Rosano, J. Soc. Cosmet. Chem. 25, 601, 1974.
E. Berry and H. J. Kamack, Proceedings 2nd International Congress of
59. L. M. Prince (Ed.), Microemulsions, Theory and Practice, Academic
Surface Activity, Vol. IV, Butterworths, London, 1957, p. 196; (c) C. L.
Press, New York, 1977.
Prasher, Crushing and Grinding Process Handbook, Wiley, New York,
60. J. M. Wood and J. H. Collett, Drug Dev. Ind. Pharm. 9, 93, 1983.
1987, Chapter 6.
61. C. Washington, Int. J. Pharm. 58, 1, 1990.
19. J. L. Zatz and R.-Y. Lue, J. Pharm. Sci. 76, 157, 1987.
62. K. Morimoto, A. Magayasu, S. Fukanoki, K. Morisaka, S.-H. Hyon, and
20. M. I. Zapata, J. R. Feldkamp, G. E. Peck, J. L. White, and S. L. Hem,
Y. Ikada, Pharm. Res. 6, 338, 1989.
J. Pharm. Sci. 73, 3, 1984.
63. C. M. Ofner III and H. Schott, J. Pharm. Sci. 75, 790, 1986.
21. S. C. Mehta, P. D. Bernardo, W. I. Higuchi, and A. P. Simonelli, J. Pharm.
64. C. M. Ofner III and H. Schott, J. Pharm. Sci. 76, 715, 1987.
Sci. 59, 638, 1970.
65. J. H. Kou, G. L. Amidon, and P. L. Lee, Pharm. Res. 5, 592, 1988.
22. K. H. Ziller and H. Rupprecht, Drug Dev. Ind. Pharm. 14, 2341, 1988.
66. P. Casparis and E. W. Meyer, Pharm. Acta Helv. 10, 163, 1935.
23. J. S. Lucks, B. W. Müller, and R. H. Müller, Int. J. Pharm. 58, 229, 1990.
67. H. B. Kostenbauder and A. Martin, J. Am. Pharm. Assoc. Sci. Ed. 43,
24. B. D. Tarr, T. G. Sambandan, and S. H. Yalkowsky, Pharm. Res. 4, 162,
401, 1954.
1987.
68. A. H. C. Chun, M. S. Thesis, Purdue University, Purdue, Ind., June 1956.
25. S. S. Davis and P. Hansrani, Int. J. Pharm. 23, 69, 1985.
69. W. C. Ling, J. Pharm. Sci. 67, 218, 1978.
26. E. Shotton and R. F. White, in P. Sherman (Ed.), Rheology of Emulsions,
70. A. R. Fassihi and M. S. Parker, J. Pharm. Sci. 77, 876, 1988.
Pergamon Press, Oxford, 1963, p. 59.
71. M. Katz, in E. J. Ariens (Ed.), Drug Design, Academic Press, New York,
27. J. A. Serrallach and G. Jones, Ind. Eng. Chem. 23, 1016, 1931.
1973.
28. J. H. Schulman and E. G. Cockbain, Trans. Faraday Soc. 36, 651, 661,
72. J. T. Carstensen, Drug Dev. Ind. Pharm. 10, 1277, 1984.
1940.
73. R. A. Kenley, M. O. Lee, L. Sukumar, and M. F. Powell, Pharm. Res. 4,
29. Atlas Powder Co., A Guide to Formulation of Industrial Emulsions with
342, 1987.
Atlas Surfactants, Atlas Powder Co., Wilmington, Del., 1953.

Coarse Dispersion Martin

Uploaded by

Copyright:

Available Formats

Coarse Dispersion Martin

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Coarse Dispersion Martin

Uploaded by

Copyright:

Available Formats

P1: Trim: 8.375in × 10.

CHAPTER 17: COARSE DISPERSIONS 411

412 MARTIN’S PHYSICAL PHARMACY AND PHARMACEUTICAL SCIENCES

phase and dispersion medium, respectively, g is the acceler-

CHAPTER 17: COARSE DISPERSIONS 413

414 MARTIN’S PHYSICAL PHARMACY AND PHARMACEUTICAL SCIENCES

CHAPTER 17: COARSE DISPERSIONS 415

Fig. 17–3. Caking diagram, showing the floc-

416 MARTIN’S PHYSICAL PHARMACY AND PHARMACEUTICAL SCIENCES

CHAPTER 17: COARSE DISPERSIONS 417

Fig. 17–4. The sequence of steps involved in the formation of a

(Vanderbilt Co.), and a combination of bentonite and sodium

418 MARTIN’S PHYSICAL PHARMACY AND PHARMACEUTICAL SCIENCES

CHAPTER 17: COARSE DISPERSIONS 419

Ziller and Rupprecht22 designed a control unit to mon-

420 MARTIN’S PHYSICAL PHARMACY AND PHARMACEUTICAL SCIENCES

CHAPTER 17: COARSE DISPERSIONS 421

and because 1 cal = 4.184 joules,

422 MARTIN’S PHYSICAL PHARMACY AND PHARMACEUTICAL SCIENCES

Fig. 17–9. Schematic of oil droplets in an oil–water emulsion, show-

A hydrophilic Tween can be combined with a lipophilic

CHAPTER 17: COARSE DISPERSIONS 423

whether a surfactant is an emulsifier, wetting agent, deter- PHYSICAL STABILITY OF EMULSIONS

424 MARTIN’S PHYSICAL PHARMACY AND PHARMACEUTICAL SCIENCES

CHAPTER 17: COARSE DISPERSIONS 425

426 MARTIN’S PHYSICAL PHARMACY AND PHARMACEUTICAL SCIENCES

this method unsatisfactory because the globules can undergo

CHAPTER 17: COARSE DISPERSIONS 427

428 MARTIN’S PHYSICAL PHARMACY AND PHARMACEUTICAL SCIENCES

lower is the viscosity when compared with a system hav-

CHAPTER 17: COARSE DISPERSIONS 429

430 MARTIN’S PHYSICAL PHARMACY AND PHARMACEUTICAL SCIENCES

Fig. 17–14. Representations of gel structures. (a) Flocculated par-

CHAPTER 17: COARSE DISPERSIONS 431

EXAMPLE 17–7 property is important because diffusion of drugs in hydrogels

432 MARTIN’S PHYSICAL PHARMACY AND PHARMACEUTICAL SCIENCES

CHAPTER 17: COARSE DISPERSIONS 433

undesirable property of drying out when not stored properly

Hydrophilic Properties of Semisolids

434 MARTIN’S PHYSICAL PHARMACY AND PHARMACEUTICAL SCIENCES

CHAPTER 17: COARSE DISPERSIONS 435

F to change the ointment into a w/o cream. At G, the base is

436 MARTIN’S PHYSICAL PHARMACY AND PHARMACEUTICAL SCIENCES

where M0 is the initial amount of drug in suspension. Equa-

5 M0 from the calculated values of kobs using equation (17–22). (From A.

6 6 profile over the pH range of 2 to 6, with a minimum rate near

k = ko + kH [H+ ] + kOH [OH− ] (17–22) k = exp[22.5 − (17,200/1.9872 × 313)]

CHAPTER 17: COARSE DISPERSIONS 437

The release of a solubilized drug from emulsion-type

438 MARTIN’S PHYSICAL PHARMACY AND PHARMACEUTICAL SCIENCES

CHAPTER 17: COARSE DISPERSIONS 439

For lidocaine, according to equation (17–29),

The total amount released from the emulsion consists of an

440 MARTIN’S PHYSICAL PHARMACY AND PHARMACEUTICAL SCIENCES

You might also like