Oil-in-Water Nanosized Emulsions for Drug Delivery and Targeting. Tamilvanan Shunmugaperumal

to determine long‐term product stability.

The manufacturers of new colloidal products (nanosized emulsions) have to be aware of the best manufacturing techniques, limitations of producing new products and efficacy of the final administered product (Margreiter 2002). Because emulsions that are easy to produce on a laboratory‐scale can be much more difficult to mass produce. The lab‐designed product does not always come with an acceptable range of built‐in invulnerability to variable storage conditions and viable shelf life of the final marketed product. Worryingly, MS nanosized emulsion droplets are notable for the size‐related improved stability and with smaller sizes the formulated products show better medium‐term stability (Medlicott et al. 2004). They are also worth considering for regular use since they have rapid API release and viable API partition coefficients (Chen et al. 2004), say from interior to interface and thus to bulk, which is primarily because of the exceptionally large surface area of nanospheres. Furthermore, adaptation is possible as the surface fluidity of interface emulsifiers can be selectively modified. In terms of API delivery, nanosized emulsions have been reported to have a particular favourable predisposition for vascular wall and capillaries (Mizushima 1996).

      The o/w nanosized emulsions are nanometric‐sized emulsions, typically exhibiting diameters of up to 500 nm or often quoted as being 400–800 nm. However, particles in this range tend to be thermodynamically unstable non‐self forming requiring mechanical energy input and are opaque. Nanosized emulsions are also frequently known as miniemulsions, fine‐dispersed emulsions, submicron emulsions and so forth, but are all characterized by a great stability in suspension due to their very small size, essentially the consequence of significant steric stabilization between droplets, which goes to explain why the Ostwald ripening is the only adapted droplet destabilization process (detailed below).

       1.1.2.2. Ostwald Ripening‐Adapted Droplet Destabilization Process for the Greater Stability of Nanosized Emulsions

The main particularity of nanosized emulsions, making them prime candidates for nanoparticle engineering, is their great stability of droplet suspension. A kinetic stability that lasts for months, stability against dilution or even against temperature changes, totally unlike the (thermodynamically stable) microemulsions. Emulsions are thermodynamically unstable systems, due to the free energy of emulsion formation (ΔG_f) greater than zero. The large positive interfacial energy term (λΔA) outweighs the entropy of droplet formation (TΔS_f), also positive. The terms λ and ΔA, respectively represent the surface tension and the surface area gained with emulsification. Emulsion instability is therefore induced by the positive sign of ΔG_f [Eq. (1.2)].

(1.2)

      Accordingly, the physical destabilization of emulsions is related to the spontaneous trend towards a minimal interfacial area between the two immiscible phases. Therefore, a minimization of interfacial area is attained by two mechanisms:

      1 Flocculation followed mostly by coalescence, and

      2 Ostwald ripening.

In nanosized emulsion systems, flocculation is naturally prevented by steric stabilization, essentially due to the sub‐micrometric droplet size. In short (Napper 1983; Tadros 1982; Tadros et al. 2004), when interfacial droplet layers overlap, steric repulsion occurs, from two main origins. The first one is the unfavorable mixing of the stabilizing chain of the adsorbed layer, depending on the interfacial density, interfacial layer thickness δ, and Flory–Huggins parameter χ_1,2 (which reflects the interactions between the interfacial layer and solvent). The second one is the reduction of the configurational entropy, due to the bending stress of the chains, which occurs when inter‐droplet distance h becomes lower than δ.

Generally, the sum of the energies of interaction U_T adopts a typical shape of systems wherein molecules repel and particles attract each other, showing a weak minimum, around h = 2δ, and a very rapid increase below this value (see Fig. 1.1 for illustration). The depth of the minimum |U₀| will induce predispositions for coagulate in the colloidal suspension, that is to say, it is intimately linked to the stability of the suspension. |U₀| is shown to be dependent on the particle radius, the Hamaker constant A, and the adsorbed layer thickness δ, with the result that the higher the δ/r ratio, the lower the value of |U₀|. Now, in the case of nanoemulsion droplets, δ/r becomes very high in comparison with macroemulsions, which in the end totally inhibits its ability to coagulate. On the other hand, it is worth noting that the small droplet sizes also induce stabilization against sedimentation or creaming, in so far as the droplets are solely under the influence of the Brownian motion.

Taking all this into account, the destabilization of nanosized emulsions is due only to a mass transfer phenomenon between the droplets through the bulk phase, well described in the literature (Taylor 1998) as Ostwald ripening in emulsions. At the origin of this destabilization process, the differences, however slight, of the droplet radius induce differences in chemical potential of the material within the drops. The reduction of free energy in the emulsion will result in the decrease of the interfacial area, and therefore in the growth of the bigger emulsion droplets at the expense of the smaller ones. The dispersed phase migrates through the bulk from the smaller droplets to the bigger ones, owing to the higher solubility in the bulk of the smaller droplets. Ostwald ripening is initiated and will increase throughout the process. As an illustration and under the assumption that only one component composes the dispersed phase, the solubility, C(Γ), of the dispersed material throughout the dispersion medium is expressed as a function of the droplet radius r, from the Kelvin equation (Skinner and Sambles 1972) [Eq. (1.3)],

Figure 1.1. Influence of emulsion droplet radius on steric stabilization.

      [Adapted from Anton et al. (2008).]

(1.3)

      where C_∞ is the bulk solubility of the dispersed phase, M its molar mass, and ρ its density.

In most studies, the follow‐up of Ostwald ripening as the temporal evolution of the droplet diameter still remains well fitted, even under the approximations involved in Eq. (1.3). In addition, the literature provides a number of theories dealing with calculations of the rate of ripening, such as the most famous (and complete) given by Lifshitz and Slezov (1959, 1961) and Wagner (1961), the so called LSW theory. Besides the consideration of Eq. (1.3), the diffusion of dispersed materials through the continuous medium is assumed to be diffusion‐controlled, i.e., crossing the interface with ease. Details on LSW theories are fully developed and discussed in the literature (Dunning 1973; Kahlweit 1975; Taylor 1998) leading to the commonly used expression of the ageing rate, ω, in Eq. (1.4),

(1.4)

      where