PREPARATION OF MULTIPLE EMULSIONS

PREPARATION OF MULTIPLE EMULSIONS – A LITREATURE REVIEW Chang Hui Quin1 1,2,3

Ida Idayu Muhamad2

Abdul Halim Bin Mohd Yusof 3

Bioprocess Engineering Department , Faculty of Chemical Engineering and Natural Resources Engineering Universiti Teknologi Malaysia, 81310 Skudai, Johor, Malaysia

Abstract Emulsions are disperse systems of two immiscible or poorly miscible liquid phases. Emulsion can be classified as simple oil-in-water (O/W) or water-in-oil (W/O) emulsions and multiple water-inoil-in-water (W/O/W) or oil-in-water-in-oil (O/W/O) emulsions. W/O/W emulsions had been used as drug delivery system (DDS).Preparation of monodispersed multiple emulsion is important in DDS to improve their stability and to facilitate control of their properties. This review described three methods to prepare multiple emulsions. The three methods are homogenisation, microchannel and membrane emulsification. Membrane emulsification has great potential to produce monodisperse emulsions. Advantages and disadvantages of direct and premix membrane emulsification were compared.Experimental studies which have focused mainly on investigation of process parameters and their influence on the membrane emulsification process are highlighted . Keywords: Multiple emulsion; Membrane emulsification; process parameters

1. Introduction An emulsion consists of at least 2 immiscible liquids (usually oil and water, but not always), with one of the liquids being dispersed as small spherical droplets in the other. Emulsions can conveniently be classified according to the spatial organization of the oil and water phases. A system that consists of oil droplets dispersed in an aqueous phase is called an oil-in-water (O/W) emulsion, whereas a system that consists of water droplets dispersed in an oil phase is called a water-in-oil (W/O) emulsion. The substance that makes up the droplets in an emulsion is referred to as the dispersed phase, whereas the substance that makes up the surrounding liquid is called the continuous phase. In addition to the simple O/W or W/O emulsions described previously, it is also possible to prepare various types of multiple emulsions, for example, oil-in-water-in-oil (O/W/O) or waterin-oil-in-water (W/O/W) emulsions. Emulsions are thermodynamically unfavorable systems that tend to break down over time due to a variety of physicochemical mechanisms, including gravitational separation, flocculation, coalescence, and Ostwald ripening. Consequently, they are different from

microemulsions, which are thermodynamically stable systems. It is possible to form emulsions that are kinetically stable for a reasonable period of time by including substances known as stabilizers, for example, emulsifiers or texture modifiers (McClements et al.2007). 2. Drug - delivery system Water-in-oil-in-water (W/O/W) emulsions have high potential for applications in the field of pharmaceutical, cosmetics, food, and chemical industries. In particular, their potential pharmaceutical applications include use as vehicles for prolonged delivery systems of hydrophilic drugs, e.g., anticancer and peptide drugs. Internal aqueous droplets can store water-soluble drugs for controlled release or targetable delivery. An effective way to improve their stability and to facilitate control of their properties is through the preparation of monodisperse W/O/W emulsions (Schubert and Lambrich, 2005).Higashi et al. used membrane emulsification for the preparation of W/O/W emulsions as a vehicle for the delivery of cancer treatment drugs. Ono et al. prepared W/O/W emulsions containing insulin for oral intake.

Corresponding author: Chang Hui Quin, e-mail: [email protected]

3. Routes to fabricate emulsions (Micronsized emulsions)

is forced into the continuous phase through microchannels manufactured via photolithography (Leal-Calderon et al.2007).

3.1 Homogenisation

One of the disadvantages of homogenisation is the energy input is orders of magnitude higher than is theoretically necessary. Another disadvantage of these methods is the relatively large droplets size distribution they yield (Kim and Schroën 2008).

Basically, there are two types of microchannel (MC) emulsification devices: (a) grooved MC, which consists of a microfluidic channel array with a slit-like terrace on a silicon chip, and generally enables the production of single micrometer-sized droplets, with a relatively low throughput capacity, and (b) straight-through MC, which is an array of channels vertically microfabricated on a silicon chip, generally producing monodisperse droplets with average droplet diameters lower than 30 µm and considerable throughput capacity, which has been scaled up to several tens of milliliters per hour (Neves et al.2008). As for membrane emulsification, an O/W emulsion is produced using hydrophilic microchannels, whereas producing a W/O emulsion requires a hydrophobic device.

3.2 Microchannel emulsification

3.3 Membrane emulsification

Emulsion droplets with diameters of 0.1–10 µm have diverse applications, including foods, cosmetics, pharmaceuticals, and chemicals. Monodisperse emulsions with very narrow size distributions can improve stability against droplet coalescence, enabling us to more easily clarify many important emulsion properties. In addition, many important potential emulsion uses require monodisperse emulsions that are precisely controlled in size. Interest in microfluidic techniques for generating individual emulsion droplets has increased in the last decade (Kobayashi et al.2007).

Membrane emulsification consists of forcing the dispersed phase to permeate into the continuous phase through a membrane having a uniform pore size distribution. The dispersed phase is pressed perpendicular to the membrane while the continuous phase is flowing tangential to the membrane (Fig. 1) (Leal-Calderon et al.2007). Although easy in principle, membrane emulsification is dependent on many parameters such as membrane properties, fluxes, and formulation, all influencing the emulsion size distribution. To obtain a monodisperse emulsion, the membrane pores must themselves have a narrow size distribution. Usually, the drop size is proportional to the pore size .The dispersed phase should not wet the membrane coating and consequently a hydrophilic membrane should be used to produce an oil-in-water (O/W) emulsion (Leal-Calderon et al.2007).

Usually micron-sized emulsions are made from a premix emulsion, which is produced by mixing gently, followed by homogenisation to further reduce the droplet size. In general, homogenisation is an intense process: it introduces a large amount of energy into the premix emulsion to break up the droplets into smaller ones (Kim and Schroën 2008).

Microchannel technology allows fabrication of monodisperse emulsion with an average droplet diameter ranging from 10 to 100 µm. The principle is reminiscent of membrane emulsification. The dispersed phase

Figure 1. Schematic principle of membrane emulsification (Leal-Calderon et al.2007)

4. Direct versus emulsification

premix

membrane

Membrane emulsification (ME) methods are depicted schematically in Fig.2.In conventional direct ME (Fig.2a), fine droplets are formed in situ at the membrane / continuous phase interface by pressing a pure dispersed phase through the membrane. In order to ensure a regular droplet detachment from the pore outlets, shear stress is generated at the membrane/continuous phase interface by recirculating the continuous phase using a low shear pump (Fig.3a) or by agitation in a stirring vessel (Fig.3b).The rate of mixing should be high enough to provide the required tangential shear on the membrane surface, but not too excessive to induce further droplet break up. Another approach uses systems equipped with a moving membrane, in which the droplet detachment from the pore outlets is stimulated by rotation or vibration of the membrane within a stationary continuous phase (Fig.3c).Even in the absence of any tangential shear, droplets can be spontaneously detached from the pore outlets at small dispersed phase fluxes (Fig.3d),particularly in the presence of fast adsorbing emulsifiers in the continuous phase and for a pronounced noncircular cross section of the pores. However, there are several disadvantages of direct ME and this lead to implementation of

‘premix’ME in which a preliminarily emulsified coarse emulsion (rather than a single pure dispersed phase) is forced through the membrane (Fig.2b).This is achieved by mixing the two immiscible liquids together first using a conventional stirrer mixer, and then passing this preliminarily emulsified emulsion through the membrane. If the dispersed phase of feed emulsion wets the membrane wall and suitable surfactants are dissolved in both liquids phases, the process may result in phase inversion, i.e., a coarse oilin-water (O/W) emulsion may be inverted into a fine W/O emulsion (Fig.2c) and vice versa (Williams and Goran T, 2005). Two systems were used for the premix ME study. The first was cross-flow system, in which the coarse emulsion was diluted by permeation into pure continuous phase or diluted emulsion recirculating at the lowpressure side of the membrane. In the subsequent works, a dead-end system was used, in which the fine emulsion was withdrawn as a product after passing through the membrane, without any recirculation and or dilution with the continuous phase. There are several advantages and disadvantages of premix ME compared to direct ME which are listed in table 1 and table 2 (Williams and Goran T, 2005).

Fig.2. Schematic diagram of membrane emulsification methods (Williams and Goran T, 2005)

Fig.3. Membrane emulsification systems for controlling hydrodynamic conditions near the membrane surface (Williams and Goran T, 2005)

Table 1 Advantages and disadvantages of direct membrane emulsification (Williams and Goran T, 2005) Advantages Very narrow droplets size distributions

Disadvantages Relatively low maximum dispersed phase flux Low productivity Long production time Suitable for relatively diluted emulsions with dispersed contained up to 30 vol.%

Table 2 Advantages and disadvantages of premix membrane emulsification (Williams and Goran T, 2005) Advantages Easily prepared(Experimental set-up simpler)

Disadvantages Higher droplets polydispersity

Optimal transmembrane fluxes are higher than direct ME Process is easier to control and operate than direct ME,since the driving pressure and emulsifier properties are not so critical for the successful operation as in the direct ME.

High throughput

5. Process parameters that influenced direct membrane emulsification The droplet formation in membrane emulsification is influenced by numerous process parameters. Schrӧder produced o/w emulsions to study the influence of various parameters on the result of the emulsification process. He showed that the wetting properties of the membranes are of great importance to the success of the emulsification process. For a narrow droplet size distribution, the membrane surface has to be wettable by the continuous

phase. The pore size of the membrane exerts the most dominant influence on the droplet size distribution. A constant ratio of Sauter diameter and mean pore size for different pore sizes can be observed at otherwise comparable conditions. Schrӧder found a ratio of about 3.5 at wall shear stresses above 50 Pa using ceramic membranes to disperse rape seed oil in water containing 0.5% of the surfactant Tween® 20. Other authors found different values due to different process conditions, e.g. lower wall shear stresses (Schubert and Lambrich, 2005).

6. Process parameters that influenced premix membrane emulsification Like in membrane emulsification in shearing regime, premix membrane emulsification is characterised by the droplet size distribution or the Sauter diameter and the flux of the entire emulsion. The process can be influenced by the membrane used for the production of the fine emulsion, the properties of the coarse emulsion and the pressure applied to this coarse emulsion. According to Altenbach-Rehm et al., the flux increases with decreasing dispersed phase fraction in the coarse emulsion and a higher pressure causes a higher emulsion flux. At low-pressure, dispersed phase fraction has a strong influence on the Sauter diameter, whereas with increasing pressure, this influence becomes less. Further, parameters influencing the emulsification process, e.g. the coarse emulsion, were investigated by Suzuki et al . Suzuki and co-workers reported a dependence of the flux and the final Sauter diameter on the process conditions applied during the production of the coarse emulsion. In the case of o/w emulsions, a lower circumferential speed while preparing the coarse emulsion resulted in a higher flux through the membrane. If premix membrane emulsification is combined with a phase inversion, there is no evidence that the applied pressure has any influence on the Sauter diameter. A higher disperse phase fraction in the final emulsion yields larger Sauter diameters. The flux decreases with increasing disperse phase fraction and with decreasing pressure.

7. Conclusions Application of multiple emulsions in the field of pharmaceuticals had been described. Potential pharmaceutical applications include use as vehicles for prolonged delivery systems of hydrophilic drugs, e.g., anticancer and peptide drugs. An effective way to improve their stability and to facilitate control of their properties is through the preparation of monodisperse W/O/W emulsions. Three routes to fabricate emulsions had been described. All the investigations carried out so far show that membrane emulsification offers great potential in manufacturing ‘made to measure’ emulsions and other solid particulates. The process is reliable, and suitable to large-scale productions. Both single (W/O or O/W) and multiple (W/O/W, O/W/O) emulsions, with various droplets sizes ranging from 0.8 to over 100 µm, and a typical coefficient of variation of 1015%,have been successfully prepared by employing different pore sizes and types of membrane. Direct membrane emulsification can be a specially attractive techniques for small-scale manufacture of low viscosity, low concentration emulsion products, due to its high capability of droplet size and distribution controls but limited emulsifying rate. Premix membrane emulsification is a technique potentially suitable for large-scale manufacture of high concentration emulsion products, due to high emulsifying rate and simple operation. Finally, several process parameters and their influence on the membrane emulsification process have been explained. Acknowledgement The authors wish to thank supervisor and co-supervisor for their support and guidance.

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