Technical Brief 2011 Volume 2
Emulsion Stability and Testing
Emulsions encompass a vast num-
ber of everyday materials and prod-
ucts including foodstuffs, personal
care items, and pharmaceuticals.
Topical emulsions of both the oil-
in-water (O/W) and water-in-oil
(W/O) types are commonly used
to improve aesthetics and ease of
application. Emulsions may also
be used to deliver multiple active
pharmaceutical ingredients (APIs)
of differing solubilitys, or present
an API in a format that improves
the distribution and/or permeation
on application, or improve patient
compliance for aesthetic reasons.
However, as emulsions are inher-
ently thermodynamically unstable,
understanding the theoretical fac-
tors influencing emulsion stability
is critical to the emulsion formu-
lator.
Emulsion Stability
The process by which an emulsion
completely breaks (coalescence),
i.e., the system separates into bulk
oil and water phases, is generally
considered to be governed by four
different droplet loss mechanisms,
i.e., Brownian flocculation, cream-
ing, sedimentation flocculation
and disproportionation, shown
schematically in Figure 1. The first
three are the primary methods by
which emulsions are destabilized
but all four processes may occur
simultaneously and in any order1, 2.
The processes of creaming, floc-
culation and coalescence are well
demonstrated by taking an emul-
sion of limited stability and centri-
fuging it at low speeds or various
lengths of time. Initially, for oils
with a density less than water (this
will be assumed unless otherwise
noted in this Technical Brief), a
rising of the cream is observed.
Then, as larger droplets rise and
concentrate, they begin to appear
at the top. Finally, the drops co-
alesce to form a separate layer of
oil on top.
Creaming derives its name from
the most commonly known ex-
ample of a de-emulsification pro-
cess the separation of milk into
its cream and skim milk compo-
nents. Creaming is not an actual
breaking but a separation of the
emulsion into two emulsions, one creaming rate of < 1 mm per day be rigorously separated. Neverthe-
of which (the cream) is richer in is considered negligible. less, an estimate of the relative
the disperse phase than the other. rates of each type of flocculation
Flocculation can be generally de-
Creaming is the principal process can be made6 from:
fined as the aggregation of drop-
by which the disperse phase sepa- max = 2 ( o) g r4 / 3 kbT
lets to give 3-D clusters without
rates from an emulsion and is typi- coalescence occurring. Impor- where k is the Boltzmann con-
cally the precursor to coalescence. b
tantly, all droplets maintain their stant and T is absolute tempera-
The creaming rate (or settling rate own integrity and remain as totally ture (Kelvin).
for disperse phases more dense separate entities. It results when
than the continuous phase) can be there is a weak, net attraction be- When max >10, Brownian aggre-
estimated from the Stokes equa- tween droplets and arises through gation is negligible; when max <
tion: various mechanisms3-5 the discus- 0.1 sedimentation aggregation is
= 2 r2 ( o) g / 9 sion of which is beyond the scope negligible.
of this Technical Brief. Because the magnitude of the
where, is the creaming (settling)
Flocculation may be subdivided forces involved is different for the
rate, r is the droplet radius, is two flocculation processes, the
the density of the droplet, o is the for convenience into two general
categories: that resulting from structure of the 3-D droplet clus-
density of the dispersion medium, ters is different.
is the viscosity of the dispersion sedimentation aggregation and
medium (continuous phase) and that from Brownian motion aggre- Finally, flocculation may also be
g is the local acceleration due to gation of the droplets. In polydis- divided into fast flocculation and
gravity. perse (real) emulsions, droplets slow flocculation7. The former oc-
of different size cream at different curs when the smaller droplets
The density difference, ( o), rates and this leads to a tendency disappear more rapidly than the
is negative for creaming (an O/W for the faster-moving (larger) drop- larger ones as a result of the dif-
emulsion) but positive for settling lets to collide with and potentially ferent rates of movement under
(a W/O emulsion). The Stokes trap, slower moving smaller drop- gravity or in forced convection,
equation shows that creaming is lets. In sedimentation aggregation leading to an increased collision
inhibited by a small droplet ra- it is assumed that all the paths in rate (orthokinetic aggregation).
dius, a highly viscous continuous sedimentation are vertically linear; The latter occurs when the build-
phase and a low density difference Brownian aggregation is the result up of large metastable structures
between the oil and water phases. of random Brownian movement slows first as a result of the energy
Substituting typical values into of the droplets. In both cases a barrier between droplets and then
the equation, i.e., r ~ 1 , ~ frequency factor for sedimentation the formation of droplet-free spac-
0.2 gcm-3 and ~ 1 mPas gives encounters can be defined4. Both es between aggregates and the
a creaming rate of ~ 5 cm per processes occur simultaneously in heavier aqueous phase O/W emul-
day which is not insubstantial. A a typical emulsion and so cannot sions; the consequence is called
hindered creaming.
Figure 1
Disproportionation is a process
SCHEMATIC OF MECHANISMS LEADING TO often referred to as Ostwald rip-
COALESENCE OF AN OIL-IN-WATER EMULSION ening that is dependent on the
diffusion of disperse phase mol-
Air
ecules from smaller to larger drop-
Oil lets through the continuous phase.
Coalescence Water Coalescence The pressure of dispersed material
is greater for smaller droplets than
larger droplets as shown by the La-
place equation:
Creaming Creaming P = 2/r
where, P is the Laplace pressure,
Sedimentation Flocculation is the surface tension and r is the
droplet radius.
This pressure differential between
small and large droplets consti-
tutes the driving force for dif-
Disproportionation Brownian Flocculation fusion, but the rate of diffusion
Original depends on the solubility of the
Emulsion dispersed phase in the continu-
Particle Sciences ous phase. The higher the disperse
2011 Particle Sciences, Inc. All rights reserved.
phase volume, the greater its rela-
tive vapor pressure (and thus the
solubility) will be, as given by the
Kelvin equation:
ln [Po / P] = 2 Vm/rRT
where, P is the vapor pressure of
the liquid droplet, Po is the vapor
pressure of the bulk liquid, is the
surface tension, r is the droplet ra-
dius and V is the molar volume of
the disperse phase.
The diffusion rate is also impacted
directly by the viscosity of the con-
tinuous phase as described by the
Stokes-Einstein equation:
D = kbT/ 6r
where, D is the diffusion coeffi-
cient of a droplet and is the con-
tinuous phase viscosity.
The measurement of both the
droplet size and size distribution
of emulsions is a critical metric.
A variety of sizing techniques are
available (see PSI Technical Brief
2009 Volumes 6 and 7) but, from
Figure 1, it is obvious that image
analysis (for regular emulsions)
should be a prime candidate.
Emulsion Stability Testing
Stability testing is an integral part
of emulsion development work. A
discussion of drug stability testing
methods and kinetics is beyond
the scope of this Technical Brief
and the reader is referred to the
many excellent books and review
papers on this subject8-10.
The emulsion formulator is gener-
ally concerned with understanding
the effects of storage and shipping
conditions on shelf-life which may
include extremes of temperatures
and exposure to sunlight, vibration
and humidity. Hence, formula-
tions are stored under standard-
ized test conditions and carefully
examined at periodic intervals.
Table 1 lists general conditions
commonly and historically used to
evaluate emulsion stability, though
regulated emulsion products must
be tested in compliance with ap-
plicable ICH guidelines. Further,
although freeze-thaw has been
widely used as an accelerated path
to judge emulsion stability, it is
not truly appropriate to rely solely
on it to make those judgements.
The cycling of temperature in
freeze-thaw experiments affects
parameters other than those that
3894 Courtney St., Bethlehem, PA 18017-8920, USA
directly relate to creaming which is wetting behavior, permeation, or but it is not practical, nor neces-
the actual mechanism of emulsion leaching of components into or sary, to conduct the total battery
instability. out of the packaging material. of tests on all preliminary formu-
Laboratory batches are generally Table 2 lists properties that are lations. Typically, initial formula-
stored in glass jars to evaluate the important to fully understand, tions are screened for changes in
inherent stability of the emulsion. including the characteristics and pH, viscosity, flow behavior, odor
The use of glass jars permits easy stability of an emulsion formula- and physical separation at elevat-
observation and physical measure- tion. The number of properties ed temperatures.
ments at regular intervals. How- is quite extensive, and all the in-
Emulsions have a long history of
ever, ultimately the emulsion must strumentation required may not use and are widely used in many
also be evaluated in the intended be available to many formulators.
products encountered in everyday
final packaging, as this may im- Ideally, all these tests should be life. Understanding the theoretical
pact the stability due to interfacial conducted on final formulations considerations in emulsion formu-
lation and having the ability and
Table 1
proper instrumentation to fully
characterize and monitor stability
COMMONLY USED TEST CONDITIONS of an emulsion system is highly
FOR EMULSION STABILITY TESTING beneficial to provide a superior
product in a more time efficient
Storage Conditions Storage Period
manner.
Ambient temperature 25 C for 3 years
o
(or projected shelf-life of the product) References
1. P. Becher, Emulsions: Theory
Elevated temperature 37 oC for 6 months and 45 oC for 6 months and Practice, Reinhold Publishing
Corp., New York (1957)
Refrigerator Approximately 4 oC for 3 months 2. P. Becher (Ed), Encyclopedia of
Emulsion Technology, Volume 1:
Freeze/thaw cycles (5) Approximately -10 oC to ambient Basic Theory, Marcel Dekker, New
York (1983)
Cycling chamber 4 oC to 45 oC in 48 hours for 1 month 3. C. Cowell and B. Vincent, J.
Colloid and Interface Science, 87
Light exposure 1 month exposure to north-facing daylight 518 (1982)
or light cabinet 4. E. Dickinson and G. Stainsby,
Colloids in Food, Applied Science
Publishers, London (1982)
Table 2
5. E. D. Goddard and B. Vincent
EMULSION PROPERTIES TO BE MONITORED (eds), Polymer Adsorption and
Dispersion Stability, ACS Sym-
DURING STABILITY TESTING posium Series 240, America
Property Test Method Chemical Society, Washington DC
(1984)
pH pH meter
6. S. R. Reddy and H. S. Olger, J.
Viscosity Rotational viscometer Colloid and Interface Science, 79
105 (1981)
Flow behavior Oscillatory shear viscosity with a cone/plate rheometer
7. M. A. J. S. van Boekel and P.
Tack/Texture Extensional and compressional deformation Walstra, Colloids and Surfaces, 3
99 (1981)
Color Visual or colorimeter
8. K. A. Connors, G. L. Amidon
Odor Organoleptic and J. S. Valentino, Chemical Sta-
bility of Pharmaceuticals: A Hand-
Specific gravity Pycnometer book for Pharmacists, John Wiley,
New York (1986)
Separation Creaming value - visual or instrumental
9. W. Grimm and K. Krummen
Conductivity Conductivity meter (eds), Stability Testing in the EC,
Droplet size Microscopic examination (image analysis) Japan and the USA: Scientific
distribution and instrumental and Regulatory Requirements,
Wissenschaftliche Verlagsgesell-
Preservation Microbial challenge and/or assay schaft, Stuttgart (1993)
Vibration Shipping test or shaker table 10. J. Wells, Pharmaceutical Pre-
formulation: The Physicochemical
Active Chemical or bio-assay Properties of Drug Substances,
ingredient(s)
Ellis Horwood, Chichester (1988)
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