«SURFACTANT SYSTEMS FOR DRUG DELIVERY AND WATER EVAPORATION REDUCTION By DUSHYANT SHEKHAWAT A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE ...»
Depending on the solubility of drug in water and oil, all three types of microemulsions (i.e. oilexternal, water-external and middle-phase microemulsion) can be used for drug delivery. In the present study, Propofol (2,6-diisopropylphenol) was selected as a test drug to form water external microemulsion. Propofol is intravenous general anesthetic drug, having several favorable anesthetic characteristics, including rapid emergence from unconsciousness without drowsiness. Propofol is water insoluble and currently used in a macroemulsion form, which has various side effects. In the present study, several oil-in-water microemulsions constituting Propofol (oil), biodegradable surfactants and polymers were formulated. Various properties of these microemulsions, like particle size, stability on dilution, and pH etc. were measured as a function of time, which shows that these systems are thermodynamically stable. Anesthetic studies of these microemulsion systems were done using randomized crossover design in rats and dogs.
Retardation of water evaporation is of interest from a number of viewpoints such as in ophthalmology wherein people suffering from dry eye syndrome show very high water loss from eyes, nuclear industry wherein radioactive water from spent fuel may escape into the atmosphere, antiseptic for burned skin victims, water conservation in certain arid and dry parts of world where water is scarce etc. But, despite this need to reduce water evaporation, few efforts have been directed in finding new ways to decrease the loss of water by evaporation. One of the approaches, which are currently being used, is to spread a monolayer of long chain alcohols/acids on top of water to decrease the water evaporation. Over the years various researchers1, 2 have worked on reduction on evaporation of water by monolayers, but the maximum reduction in evaporation of water achieved by monolayers is only around 50%. Also, problem with monolayers is that they can be easily removed by winds and undergo thermal as well as biological degradation. Another approach is to use a multimolecular film of oil as a means of reducing the evaporation of water. But in this case small amount of oil does not spread so the amount of oil used is very high, which is not economical. In this work, we proposed a new approach to reduce the evaporation of water, i.e. multimolecular (duplex) films of micron or submicron thickness of oil and surfactants that spontaneously spreads on the water surface and reduce the water evaporation rate.
The following is the detailed review of colloidal drug delivery system and reduction of water evaporation.
The design and development of new drug delivery systems with the intention of enhancing the efficacy of existing drugs is an ongoing process in pharmaceutical research. It is necessary for a pharmaceutical solution to contain a therapeutic dose of the drug in a volume convenient for administration. Of the many types of drug delivery systems that have been developed, one in particular, i.e. colloidal drug delivery system has great potential for the goal in drug targeting.
A few of the most widely examined colloidal drug delivery systems are micelles, microemulsions, macroemulsions, liposomes, and nanoparticles. These colloidal systems are shown schematically in Figure 1-1. A comparison of physical properties of these colloidal drug delivery systems is given in Table 1-1.
1.1.1 Micelles A surfactant, or surface-active agent, is defined as a substance that adsorbs onto surfaces or interfaces of solutions to lower the surface or interfacial tension of the system.3 The magnitude of the lowering of the surface or interfacial tension depends on the surfactant structure, concentration, and the physico-chemical conditions of the solution (e.g. pH, salt concentration, temperature, pressure, etc.).3 Surfactants are typically amphiphatic species, meaning that they are made up of a hydrophobic component, referred to as the “tail,” and a hydrophilic component, referred to as the “head” group (see Figure 1-2). When placed in solution, surfactant molecules tend to orient in such a way as to minimize the interactions of the hydrophobic “tail” with water in aqueous solutions, or to minimize the interactions of the hydrophilic “head” with oil in organic solvents. This leads to adsorption of the surfactant molecules onto surfaces or at interfaces, and above a certain concentration, known as the critical micelle concentration or “cmc,” surfactants form aggregates known as micelles. When placed into aqueous solutions, surfactant molecules will form spherical aggregates at the cmc where the hydrophobic tails are pointed inward and removed from interaction with water molecules by the hydrophilic head groups as shown in Figure 1-2. When placed into organic solutions, surfactant molecules will form reverse micelles with the hydrophobic tails pointed outward (see Figure 1When the critical micellar concentration, or cmc, is reached, many of the physical properties of the surfactant solution in water show an abrupt change as shown in Figure 1-3.
Some of these properties include the surface tension, osmotic pressure, electrical conductivity, and solubilization. The cmc is a measure of the free monomer concentration in surfactant solutions at a given temperature, pressure, and composition. Mcbain4 first investigated the unusual behavior of fatty acid salts in dilute aqueous solution at the cmc in the 1910s and 1920s and was followed by Hartley5, 6 in the 1930s. Other evidence for surfactant aggregation into micelles was obtained from vapor pressure measurements and the solubility of organic molecules in water. The formation of colloidal-sized clusters of individual surfactant molecules in solution is known as micellization.
Normal micelles are optically isotropic and thermodynamically stable liquid solution of water and amphiphile. Micelles have low viscosity, long shelf life, and are very easy preparation method. But, micelles do not tolerate large amount of apolar species because of their very limited capacity to solubilize oil.
1.1.2 Macroemulsions It is a commonly known fact that oil and water do not mix. However, emulsifying agents, typically surfactants can be added to a mixture of oil and water to promote the dispersion of one phase in the other in the form of droplets. Over the years, emulsions have been defined in a variety of ways. Emulsions are thermodynamically unstable, heterogeneous systems, consisting of at least one immiscible liquid intimately dispersed in another in the form of droplets, whose diameters are generally in the range of 1 - 100 μm.7 There are two main types of emulsions: oilin-water emulsions, in which oil droplets are dispersed in a continuous water phase, or water-inoil emulsions, in which water droplets are dispersed in a continuous oil phase.
The most fundamental thermodynamic property of any interface is the interfacial free energy, or interfacial tension. The interfacial free energy is the amount of work necessary to create a given interface. The interfacial free energy per unit area is a measure of the interfacial tension between two phases. A high value of interfacial tension implies that the two phases are highly dissimilar in nature. There are many methods available to measure the interfacial tension between two liquids including the Du Noüy ring method, Wilhelmy plate method, drop-weight or drop-volume method, pendant drop method, spinning drop method, and Sessile drop method.3 Emulsification involves the generation of a large total interfacial area. Considering that the two phases in emulsions are not miscible, in order to generate this large interfacial area, the
interfacial tension must be lowered significantly according to the following equation:
where W is the work done on an interface, γ is the interfacial tension, and ΔA is the change in interfacial area associated with the work W. According to Equation (1-1), when a constant amount of work is applied to generate an interface, ΔA will be large if γ is small, and thus the interface will expand significantly to form smaller emulsion droplets.
As previously mentioned, the primary means by which the interfacial tension is lowered is through the addition of emulsifying agents, usually surfactants. The surfactant molecule also plays a second role in emulsions which is to stabilize the interface for a time against coalescence with other droplets and concomitant phase separation. A large number of methods have been developed to provide the energy needed to achieve complete emulsification in a given system.7Emulsion droplet size Emulsions are classified as either water-in-oil (W/O) or oil-in-water (O/W) depending on which phase is continuous and which is dispersed. The dispersed phase in emulsions, whether oil or water, is usually composed of spherical droplets within the continuous phase. These droplets may be nearly monodisperse in terms of droplet size; or they may have a wide size distribution depending on several factors.7 In most cases, the wider the size distribution, the less stable is the emulsion. In other words, emulsions with a more uniform size distribution tend to remain stable for longer time while those with wide size distribution will usually undergo Ostwald ripening, a phenomenon where larger droplets grow at the expense of smaller droplets.11 In general, emulsions with a narrow size distribution and a small mean droplet size tend to exhibit a greater emulsion stability, all other things being equal.7 The change in the size distribution with time reflects the kinetics of coalescence in emulsions.
Depending on the surfactant that is used to stabilize the emulsion, emulsions can have lifetimes ranging from hours to as long as a few years.7 In general, emulsions exhibiting a higher yield stress tend to show higher emulsion stability and shelf life.7 Emulsion droplet size is also related to the method of preparation that is employed to generate the emulsion. This is a result of the relationship between interfacial area and work that is done on the system, according to Equation (1-1). As can be seen in this equation, if the interfacial tension is constant with time, the change in interfacial area is directly proportional to the amount of work that is put into the system. Some emulsion preparation methods provide more energy (work) than others, and thereby lead to smaller droplets and higher interfacial area.
Micellar stability is another factor that affects the droplet size of emulsions.12 If the micelles are very stable, flux of surfactant monomers to the interface of droplets will be low, resulting in a higher interfacial tension at the droplet surface and a large droplet size will occur as predicted by Equation (1-1). The process of monomer diffusion from the bulk to the oil/water interface is illustrated in Figure 1-4.
220.127.116.11 Viscosity of emulsions The viscosity, or resistance to flow, of emulsions could be considered as one of their most important properties. This is true from both a practical and a theoretical viewpoint. In a practical sense, certain cosmetic or even food emulsions are only desirable at a specific viscosity (e.g.
lotions, milk, salad dressings, etc.). Manipulation of emulsion viscosity to achieve the desired product specifications is not a trivial matter. From a theoretical perspective, the viscosity measurements can be used to provide insightful information about the structure and possibly the stability of an emulsion. The overall emulsion stability is affected by the following factors:7, 13
• Viscosity of the external phase
• Concentration (i.e., volume fraction) of the internal phase
• Viscosity of the internal phase
• Nature of the emulsifiers
• Surface viscoelasticity of the interfacial film formed at the oil/water interface
• Droplet size distribution 18.104.22.168 Emulsion stability As mentioned previously, one of the most important parameters in emulsification processes is emulsion stability. For example, milk is a natural emulsion of the O/W. If the stability of milk was only a week or two, the milk would have to be shaken vigorously before pouring.
However, in this case nature has provided us with a stable emulsion. Another common example is shampoo, another emulsion. It would be inconvenient if the shampoo were not a stable emulsion, since shaking would be necessary. There are also cases where it is necessary to break down unwanted, naturally occurring stable emulsions. Such examples are the W/O type emulsions which build up in oil storage tanks, or the O/W type emulsions that arise in effluent waters.