Accelerated stability testing of emulsions

274 Groves: Accelerated Stability Testing of Enzulsions

ACCELERATED STABILITY TESTING OF EMULSIONS *

By M. J. GROVES

Introduction Becherl reviewed the various definitions of an emulsion

to be found in the literature and proposed the following as a basis for discussion. ‘An emulsion is a heterogeneous system consisting of at least one immiscible liquid inti- mately dispersed in another in the form of droplets whose diameters in general exceed 0.1 pm. Such systems possess a minimum stability which may be accentuated by such additives as surface-active agents, finely divided solids, etc.’

In general, this definition is satisfactory, but it is useful to accept the qualification proposed by McLachlan2 who suggested that one of the phases could be solid at ambient temperatures, although at the time of mixing the two phases would both be liquid. This particular qualification applies to many pharmaceutical and cosmetic products which consist of, for example, low-melting point fats and waxes dispersed in water. These are true liquid/liquid systems at elevated temperatures, i.e. during emulsifica- tion, but cool to give solid/liquid dispersions.

It is worth remembering the importance of some of the more familiar emulsions and hence the economic necessity to assess stability. Milk and dairy products, ice cream, asphalt, rubber latex, polymer emulsions, cutting oils and many natural products obtained from plants and animals are all examples of emulsions used in large quantities. However, this paper is mainly concerned with the pharmaceutical and cosmetic products intended for use as vehicles for medicaments or perfumes and emulsions containing pesticidal materials for application to plant and animal surfaces.

Instability of emulsion systems Adam3 noted that a fundamental property of liquid

surfaces is that they tend to contract to the smallest possible area. In thermodynamic terms the interfacial free energy will be at a minimum, and therefore, the system will be at its most stable when the area of the surface between two immiscible liquids is also at a minimum. The greater the surface of the dispersed liquid in the continuous phase, the greater is the interfacial free energy, and hence the greater the tendency to reduce the interfacial area. It follows, therefore, that an emulsion of two immiscible liquids is, by definition, unstable. The purpose of the additives such as surface-active materials, viscolisers, etc., is to improve stability and to minimise the rate of separation of the two phases.

An emulsion, therefore, cannot remain in the same state of dispersivity; a number of simultaneous or separate phenomena are changing the state of dispersion in order to reduce the interfacial area and the free energy of the system. The final state is the complete separation of the dispersed phase as a separate bulk layer. The stability of an emulsion can be defined as the inverse rate of change of the state of dispersion of the dispersed p h a ~ e . ~

Four processes are involved and perhaps the complexity of emulsion stability testing is due, at least in part, to the fact that one or more of the processes can proceed inde- pendently and simultaneously.

Flocculation.-This is reversible and is referred to as ‘creaming’ when the floccules separate from the bulk phase and rise to the top. Since particles in a concentrated emulsion are in close proximity, if not actually in contact, it is possible to visualise that the emulsion is already flocculated, instability taking place as a result of coalescence.

Aggregation.-This is reversible only with difficulty and can be visualised as irreversible creaming. In both these processes there is no change in the primary particle size, only in the number of particles which are associated together, the distances apart and the amount of the trapped continuous phase which forms a constituent part of the aggregated cream.

Cualescence.-This leads ultimately to separation of free oil phase. The process is irreversible and results in an increase of particle size.

Molecular difusim-This is slow and leads to an irreversible increase in particle size of the largest particles at the expense of the smallest. It depends on the solubility of the disperse phase in the continuous and is accelerated when the system is exposed to fluctuating temperature stress.

Coalescence is not clearly understood, although it is this process which distinguishes emulsions from suspen- sions, where there are otherwise obvious analogies between the flocculation and aggregation stages. The emulsion particles are separated by thin aqueous films which become thinner in time as the continuous phase drains away. The actual coalescence is preceded by rupture of the aqueous film to allow the oil droplets to flow together to form one larger droplet. Two views on the coalescence phenomenon have been expressed. Gillespie & Ridea15 considered that the continuous phase drained until a critical thickness was reached, at which point it ruptured. The magnitude of this thickness was thought to depend on the properties of the adsorbed film of surfactant. Robinson,‘j on the other hand, considered that an equilibrium thickness was reached between the attractive and repulsive forces. This film remains at the limit for an indefinite time until a hole forms in it caused by local displacement of surfactant, by a local temperature gradient or by some external distur- bance.

Molecular diffusion results in Ostwald ripening or growth of the larger particles at the expense of the smaller. There is also a tendency for small particles to be more soluble than bigger ones7 so the net effect is that dispersed material goes into solution from small particles and diffuses to the larger ones. The effect, in general, is less evident for many emulsion systems since the solubility of the disperse phase is often very low (Kitchener & Mussel- whites suggest that the solubility of a paraffin in water is

Presented at a symposium on ‘Accelerated Storage Tests for Pharmaceutical and Pesticidal Formula- tions’, organised jointly by the Pesticides Group and the Physicochemical and Biophysical Panel on 19 January, 1970.

Pestic. Sci., 1970, Vol. 1, November-December

Groves: Accelerated Stability Testing of Enzulsions 275

0.01 % which would seem from other indirect evidence to be an overestimate). However, some academic studies on emulsions containing dib~tylphthalate~ or carbon tetra- chloridelo in water have suggested that the effect may become important when the water solubility is relatively high compared with other oil systems.

Each one of these processes proceeds at its own rate and each can be the rate-determining step in the process of de-emu1sification.l'

GarretP suggested that the following types of instability may be manifested: creaming with or without aggregation and increase in particle diameter; aggregation (with or without creaming); increase in particle diameter or lowering of interfacial area; leading ultimately, to the production of a separate and continuous oil phase.

Knoechel & Wurster13 defined a stable emulsion system as one in which no sedimentation or creaming and no aggregation, flocculation or coalescence of the discon- tinuous phase occurs. These authors felt that since creaming decreased the interparticle distances, which could then lead to possible changes in the flocculation and coalescence rates, the rates of the above phenomena might be inter- related. However, they found that the viscosity of the continuous phase had only a slight effect on the gross stability of the systems studied.

Notwithstanding some of the finer points made in the literature as to what does or does not constitute instability, it is apparent that any observable change with time is a valid measure of emulsion transformation. Whether such changes can serve as quantitative measures for the com- parison of stabilities of dissimilar systems or whether they can be used as tools to predict changes in other observable emulsion parameters, are in themselves, questions of some importance.

Methods of assessing instability

Bulk or gross changes The effects measured result from the gross changes

which are the final result of initial changes at the particular level. These include measurement of the volume of free oil which separates out as a layer at the top of the system or the volume of flocculated or aggregated particles readily detected visually. The changes are complex in nature and therefore difficult to detect initially or accurately enough to enable kinetic considerations to be applied. On the other hand, there is little need for sophisticated equipment. This is often the method employed in development laboratories in assessing the relative stability of a series of emulsions exposed to a variety of stresses. However, although this method can be used to rank formulations, it can be an extremely slow procedure because it often takes a long time for an adequate formulation to manifest instability, perhaps by definition. Hence, other methods are sometimes required to give quicker results.

Centrifugal and ultra-centrifugal methods Obtaining results from the usual gravitational test

methods can be accelerated by the use of centrifugal force in which the volume of free oil can be measured with greater accuracy. The use of the ultra-centrifuge was described by Vold & G r o ~ t , ~ ~ - ' ' Garrett1* and Rehfeld.lQ It appears to have greater application since Vold & Groot found that most emulsion systems examined by them were too stable for the separation to occur in laboratory centri- fuges. Garrett'* used an ultra-centrifuge to differentiate between 'good' and 'bad' emulsions and suggested that ultra-centrifugation of thermally stressed emulsions would permit evaluation of rate constants of continuous-phase

separation as functions of gravitational stress, allowing the Arrhenius equation to be applied. Little direct evidence was provided for this and a number of simplifications seem to have been made, one of which was the neglect of the polyhedral shape that closely packed emulsion particles will assume. Nevertheless, this represents the first attempt to extrapolate results obtained under ultra- centrifugal conditions to those existing under normal gravitational stresses.

Vold & Groot found that initially the oil separated rapidly but that the rate slowed down on prolonged centrifugation. In their earlier work14915 they used as a quantitative measure of emulsion stability the virtually steady state which existed for a period of 20-60 min centrifugation time and obtained the percentage of free oil separated at zero time by extrapolation of the straight portion of the graph. However, this procedure neglects the decrease in the rate of oil separation on prolonged centrifugation.

Experimentally during centrifugation an emulsion system separates into free oil, cream, emulsion and free water (for an oil/water system). GrootZ0 later found that the oil separation depended upon the pressure exerted by the column of emulsion at the emulsion interface and this was proportional to the length of the emulsion column in the centrifuge tube. This can be expressed mathematically as :

dv/dt = -dA/dt = k A

where dv is the volume of oil separated in time element, dt, and A is the volume of the cream layer, dA is the decrease in the volume of the emulsion column and k' is a constant. Integration gives:

1nA = -k't + a constant.

When t = 0 the constant is In A,, i.e. the volume of the

emulsion column at t = 0. Thus log A / A , = - L k ' t .

Apart from some inconsistencies at the beginning of the centrifugation time clearly connected with acceleration up to the speed of rotation, a good linearity was established between centrifugation time and log A, enabling repro- ducible values of the rate constant to be measured. Groot suggested that this parameter could be utilised as a quantitative measure of emulsion stability and he showed that this value was unaffected by the procedure used to accelerate the system up to its final rotational velocity

Under ultra-centrifugal conditions the emulsion particles are essentially flocculated into a cream layer and are then distorted into close packing condition. The stability rate- determining process is therefore that of coalescence. Under gravitational conditions the buoyancy forces are much less ; although creaming occurs, the droplets remain spherical and are not necessarily flocculated. A simple correlation between emulsion stability under ultra-centrifugal conditions and emulsion shelf-life under gravity storage conditions would not therefore be anticipated, although it might be possible to establish some sort of empirical relationship between the two.

2.303

Dielectric measurement A study of the dielectric properties of an emulsion

system can be utilised to provide information on the internal structure and properties of emulsion systems. This property has been extensively reviewed by €lanaiz1 who defined the dielectric as the ratio of the electrical capacitance of a parallel plate condenser filled with the emulsion to that of the same system in vacuum. Kaye & Seager" pointed out that since water has a high dielectric constant


276 Groves: Accelerated Stability Testing of Emulsions

and oil a low one, the ascent of oil droplets into the upper layers of an emulsion and their replacement in the lower layers by water should produce measurable changes of dielectric in the upper and lower regions of the system. These changes were measured using a specially designed cell. The equation used for measurement of the relationship of the cell capacitance in the presence of water, the capacitance in the presence of the emulsion and the dielectric shows that, in fact, the cell capacitance is only sensitive to dielectric changes in emulsions of low conduc- tivity and cannot, for example, be utilised in emulsions prepared with ionic surfactants.

Nevertheless, these authors found the method would detect phase separation after only a few minutes in emulsion systems where no visible creaming could be detected for several days. This investigation formed the basis for a commercial instrument exploiting the principle of dielectric change, The Telray Emulsion Stability Tester. An important factor governing the rate of emulsion creaming is the globule size and a quantitative relationship was found between the log of the rate of change of dielectric and log of mean particle size. This was later exploredz3 and only appears to be applicable to relatively coarse emulsions where the majority of particles are above about 20 pm diameter. The method is capable of detecting gross changes caused by migration of oil particles within an emulsion, the characteristic feature of creaming, and although there is not a great deal of published information, the method could presumably be used to obtain quantitative information on creaming rate.

There are some limitations to the method, one of which is the exclusion of ionic materials in the emulsion. Cream- ing is an undesirable attribute of some emulsion systems, particularly those used as cosmetic or pharmaceutical products, and the device has obvious application here.

Changes in the state of dispersion Since the definition of instability involves the state of

dispersion of the dispersed phase, it follows that any method which measures the rate of change of the dispersed state is, effectively, measuring the stability or instability of the system. Methods of measuring the particle size of emulsion systems have been reviewed elsewherez4 but they can be classified as follows: (i) microscope (optical or electron). This is direct and accurate within certain limitations of sampling error but generally tedious in operation; (ii) ultra-microscope. This can be used to count particles in, D known volume or combined with inertial methods to separate particles according to their size; (iii) turbidimetric. This involves measurement of the reduction of intensity of light transmitted through a dispersion; and (iv) light scattering at some definite angle such as 90" or 15" forward. Both these methods are simple in operation but difficult in interpretation and are generally limited to determining the mean particle size, not the particle size distribution; (v) Coulter principle. This is accurate but limited t o particles larger than about 1 pm which are not flocculated in the presence of electrolyte.

These methods can therefore be used to follow the change of particle number, mean particle size or particle size distribution of an emulsion system with time. However, as noted by Groves & F r e s h ~ a t e r , ~ ~ none of these methods can be applied to an undiluted emulsion system. In all cases it is necessary to sample a system and prepare a dilution before making a measurement. I t follows that unless a system is stable enough to resist the forces that are necessarily involved in sampling and diluting, the results of the measurement are in themselves subject to doubt as to their interpretation.

Chemical methods of measuring surface area GrootZ0 in his ultra-centrifugal studies of emulsion

behaviour, showed that surfactant was desorbed from the emulsion particle surfaces at the locus of coalescence and was transported to the aqueous layer by drainage or re- sorbed at the residual interface. This observation was laterz5 extended to show how total interfacial area could be measured by treating the adsorption of the surfactant at the interface as a means of characterising the emulsion. The method was then applied to following the change of specific interfacial area of emulsions when stored. It is basically simple in theory although obviously limited to a system in which there is only one surfactant which is readily assayed by some means or another. Hill & Knight26 have recently proposed a new theory for the coalescence process from which they concluded that a system which began with a Gaussian particle size distribution would retain the distribution function, but the reciprocal of the total surface area would increase linearly with time. This idea is reminiscent of that of King & Mukherjee4 and t!ie chemical method would appear to provide a means of testing this theory.

Indirect methods It follows that, if there is a redistribution of the surfac-

tant as coalescence proceeds, the surface tension of the aqueous phase will change as the system manifests instability. For the same reason properties such as the electro- phoretic mobility should also change with time in an unstable system.

However, the most sensitive measurements of change within a system may be those connected with the rheological properties, especially, if the system has non-Newtonian flow characteristics. It is generally accepted that properties such as the characteristic shape of the flow curve, or the relative viscosity at infinite shear rates, are affected by the size of the constituent particles or their flocculation or aggregation states. Hence, any changes within a system involving these parameters should be reflected in she rheological behaviour. The quantitisation of a complex flow curve is by no means straight-forward but the flow behaviour is sensitive to changed conditions and has the considerable advantage that it can be measured on the system as a whole without the need for dilution. Shermanz7 discussed tlus at length although his objective was to predict viscosity changes over long ageing periods. Since the changes depended upon particle size he prepared emulsions of different particle size in order to obtain a picture of changes that could occur. A correlation was obtained between particle size and viscosity data so that where two systems had the same particle size distributions they would be anticipated to have the same relative viscosity. Sherman was able to predict viscosity changes over long periods of storage from the changed particle size distributions. This may have been fortuitous in some ways since the method of measuring particle size was not especially sensitive and the suggestion does not appear to have been followed up by other workers. Nevertheless, the principle of making measurements of some suitable rheological parameter does have attractions and may find future application.

Acceleration of instability

The purpose of an accelerated storage test is to increase the stresses upon a product and attempt to predict whether or not it will withstand the more normal stresses under usual conditions of storage for a sufficiently long period of time to make that product a viable commercial entity.


Groves: Accelerated Stability Testing of Emulsions 277

Although an emulsion is by definition unstable, the formulator may go to considerable lengths to make a stable product. It is the formulator who will attempt to assess a product in terms of applied stress and the method of operation is often arbitrary and empirical - a series of otherwise satisfactory formulations are prepared and the one or ones with optimum properties, including stability, are selected for further evaluation or marketing. What has to be remembered is that although it is possible to rank products in terms of relative stability, it is only rarely possible to extrapolate results from a storage test, accelerated or otherwise. It cannot be said with any conviction that this particular preparation will withstand so many weeks storage under normal room temperature conditions because it withstood so many hours under accelerated storage test conditions.

Temperature stress Low temperature

Owing to their importance in the refrigeration of milk products and the manufacture of ice cream, the structural changes which occur in emulsions exposed to very low temperatures have been studied in depth, although much less is known about the mechanisms that are involved. When an oil/water emulsion is frozen, water crystals appear which push the oil droplets into narrowing channels of unfrozen liquid between the crystals.2s The concentration of electrolytes also increases so that residual water super- cools and the growing water crystals force the oil droplets closer together until they coalesce or aggregate, depending upon the properties of the disperse phase and the emulsifier.28 Here formulation factors are clearly important but it is also worth noting that freezing rates are involved in determining whether or not a system will recover its original form on thawing.

Elevated teinperature Much less is known about changes which occur in

emulsions exposed to temperatures well above normal ambient conditions. This is despite the fact that such conditions are often used as a means of accelerating ageing and predicting long-term stability. Levius & D r o m m ~ n d ~ ~ used an optical microscope method for measuring particle size and demonstrated that, for a number of pharmaceutical systems, there was a rise in the rate of interfacial area decrease above 40"c. Between 30 and 40"c these authors found that stability was much less influenced by temperature, but below 30"c the stability decreased as the temperature fell to 4"c. As noted by Sherman31 some waterloil systems tend to invert when heated and this suggests that there is an equilibrium set up between the opposing tendencies of the emulsifiers which is displaced by temperature in favour of one type of emulsion. The solubility of the emulsifier in the two phases is involved, since it seems that there can be a redistribution between them. This has recently been highlighted by the work of S h i n ~ d a ~ ~ , ~ ~ on phase inversion temperatures.

Alternate highllow temperature fluctuation One of the most effective methods of cracking an emul-

sion is to cycle it between two extremes of temperature. One useful index of emulsion stability is the number of freeze-thaw cycles a product can withstand under a standardised set of conditions. The factors involved here are as yet incompletely understood, but probably involve a combination of the features of both high and low temperature conditions. The test has an underlying basis of realism since in practical terms, a product would be

unlikely to be stored at a steady state, but would experience fluctuating temperature stress.

Centrifugal stress Centrifuging has been used at relatively low speeds in

the dairying industry to accelerate creaming rates. MerrilP& used a low-speed centrifuge up to 3600 rev./min to apply stress when measuring the rate of separation of the internal phase and he utilised this as a quantitative index of the mechanical stability of his emulsion systems. Cockton & Wynn35 increased the stresses with speeds of 20,000 rev./min and found that the logarithm of the particle numbers decreased linearly with time. However, in general, most emulsion systems are too stable to be affected by centrifugal stresses and it remained for Garrett,l* Vold & Groot,14-17 and Rehfeldl* to demonstrate that the ultra- centrifuge was a more useful tool for the final stage of emulsion stability. In a sense the method only provides information on the coalescence process. As noted earlier an emulsion under stress in an ultra-centrifuge is in a different physical state from a system under gravitational stress or even in a slow-speed centrifuge. For example, a speed of 60,000 rev./min corresponds to about 200,000 x g . It is therefore unlikely that a centrifugal method can be used to determine the ageing behaviour of emulsions under normal conditions. This is especially true if the flocculation process is the rate-determining step in the degradation.

Shearing stress Some emulsion systems are designed to be unstable

under shearing stress. Examples of these are the cutting oils used in machining metal parts and lubricating emulsions used to assist the rolling of metal sheet and foil. Many waterloil systems are prone to revert to oil/water emulsions when subjected to shear and at least one cosmetic preparation uses this principle of reversal on application to the skin. It therefore appears to be a possibility that degradation of some emulsion systems might be accelerated by applying shear under controlled conditions. One method of achieving this would be to shear the sample under increasing shear stresses in a concentric cylinder viscometer of the Couette type or under a cone-plate arrangement such as is used in the Ferranti-Shirley viscometer. The main problem here would be to assess the degree of change or instability. Clearly, when considering the cutting or rolling of metal surfaces the failure of the preparation to lubricate or some measurement of the increase in friction might constitute a valid end-point.

Since sample sizes are generally small, measurement of particle size changes may be an alternative means of defining instability under shearing stress. In this case it would be important to remember the observation by Higl~gate~~ of the migration of particles under the cone of a cone-plate viscometer during steady shearing conditions. As noted earlier, the apparent viscosity under applicd shear stress is a complex function of particle size and factors such as flocculation state. It should therefore be possible to combine rheological measurements with acceleration of instability under shearing conditions, although to date this does not appear to have been carried out directly in order to evaluate the stability of practical formulations.

Conclusions

The very complexity of an emulsion system renders the definition of instability somewhat imprecise. A number of methods may be used to define changes within emulsion systems. However, although there are many stresses which


218 Groves: Accelerated Stability Testing of Emulsions

can be applied to accelerate these changes, the inter- relationships are extremely complex. It is not always possible to apply kinetic considerations in an attempt to extrapolate the findings to predict, for example, shelf-life under normal storage conditions. However, it is possible to classify members of a series in the likely order of resistance to a specified stress. From the formulator’s point of view, accelerated stability testing of emulsions becomes largely empirical and necessitates the selection of the optimum preparation on the basis of formulation changes favouring stability or resistance to likely stresses. It rarely

allows him to predict a useful shelf-life. Indeed, under some conditions such as ultra-centrifugation the results may be misleading. The constitution of a typical emulsion formulation is usually so complex and the interaction between the mechanisms of breakdown so devious, that the accelerated stability test results in themselves may have little relation to reality.

Chelsea College of Science and Technology, London, S.W.3

Received 28 April, 1970

References

Becher, P., ‘Emulsions: Theory and Practice’, 1965, Am. chem. Soc. Monogr. No. 162 (2nd edn) (New York: Reinhold)

McLachlan, T., Chemy Itid., 1962, p. 855 a Adam, N. K., ‘The Physics and Chemistry of Surfaces’, 1941,

(3rd edn), p. 2 (Oxford: University Press) King, A., & Mukherjee, L. N., J . Soc. chem Ind., Lond.,

Trans., 1940, 59, 185 Gillespie, T., & Rideal, E. K., Trans. Faraday Sue., 1956,

52,173 Robinson, C., ibid., 1936,32, 1424 ’ Thomson, W., Phil. Mag., 1881, 42,448 * Kitchener, J. A., & Musselwhite, P. R., ‘Emulsion Science’,

(Ed. Sherman, P.) 1968, p. 81 (London: Academic Press) Higuchi, W. I., J. pharm. Sci., 1964, 53, 405

lo Higuchi, W. I., & Misra, J., ibid., 1962, 51, 459 l1 van den Tempel, M., 1953, Thesis, Delft lZ Garrett. E. R.. J . Dharm. Sci.. 1965. 54. 1557 l3 Knoechel, E. ’L.,z & Wurster, D.’E.,‘ J. Am. pharm. Ass.

Vold, R. D., & Groot, R. C. , J. phys. Shem., Zthaca, 1962, (scient. edn), 1959, 48, 1

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Is Rehfeld, S. J., J . phys. Chem., Ithaca, 1962, 66, 1964 2o Groot, R. C., 1965, Thesis, Ultrecht 21 Hanai, T., ‘Emulsion Science’, (Ed. Sherman, P.) 1968, p. 353

22 Kaye, R. C., & Seager, H., J . Pharm. Pharmnc., 1965, 17,

23 Kaye, R. C., & Seager, H., ibid., 1967, 19,78 24 Groves, M. J., & Freshwater, D. C., J . pharm. Sci., 1968, 57,

25 Groot, R. C., Abh. dt. Akad. Wiss. Berl., 1967, 68, 566 26 Hill, R. A. W., & Knight, J. T., Trans. Puraday Soc., 1965,

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33 Shinoda, K., & Saito, H., J. Colloid Interface Sci., 1969, 30,

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Accelerated stability testing of emulsions