Nano-emulsions and Micro-emulsions: Clarifications of the Critical Differences

Abstract

Much research has been done over the past years on self-emulsifying drug delivery systems, their main interest being the simplicity of the formulation processes, the great stability of the systems and their high potential in pharmaceutical applications and industrial scaling-up. Self-emulsifying drug delivery systems are generally described in the literature indiscriminately as either nano-emulsions or micro-emulsions. Although this misconception appears to be common, these two systems are fundamentally different, based on very different physical and physicochemical concepts. Their differences result in very different stability behaviors, which can have significant consequences regarding their applications and administration as nanomedicines. This paper aims at clarifying the problem, first by reviewing all the physical and physicochemical fundamentals regarding these two systems, using a quantitative thermodynamic approach for micro-emulsions. Following these clarifications, we show how the confusion between nano-emulsions and micro-emulsions appears in the literature and how most of the micro-emulsion systems referred to are actually nano-emulsion systems. Finally, we illustrate how to clear up this misconception using simple experiments. Since this confusion is well established in the literature, such clarifications seem necessary in order to improve the understanding of research in this important field.

Preparation of nanoemulsions by phase inversion temperature (PIT)

“…Nanoemulsions are emulsions that contain very small droplets, i.e., 10-100 nm 16 , < 300 nm 29 or 20-500 nm 24 . Due to their small size, nanoemulsions often appear transparent or translucent similar to microemulsions.…”

“…These phases may be water-continuous, oil-continuous or bicontinuous, depending on the concentrations, nature, and arrangements of the molecules present. Therefore, the structures of microemulsions may be spherical, lamellar structures or bicontinuous 29,30 . Although microemulsions are thermodynamically stable, they may become unstable if some of the components undergo chemical changes during storage or if the environmental conditions are altered into a range where the system is no longer thermodynamically stable 30 .…”

Lipid-based systems as a promising approach for enhancing the bioavailability of poorly water-soluble drugs

“…Namely, according to the definition, microemulsions are thermodynamically stable systems that form spontaneously, whereas »microemulsions« formed upon diluting SMEDDS are not necessarily thermodynamically stable and may need some energy input (such as stirring or gastrointestinal motility) to be formed. Some authors therefore prefer to refer to the type IIIb formulations according to LBCS as self-nanoemulsifying drug delivery systems (SNEDDS) (26,35,46,47). According to the scientific definition, this may be a more accurate terminology, as pointed out in a recent expert review by Anton and Vandamme (47).…”

“…The characteristics differentiating SEDDS, SMEDDS and SNEDDS are presented in Table VIII; however, this terminology certainly needs clarification, as recently pointed out in an expert review by Anton and Vandamme, 2011. In general, water-free systems (SEDDS, SMEDDS, SNEDDS) are preferred for oral preparation to the regular (micro-/nano-) emulsion system due to their lower volume and increased drug stability.…”

“…It is therefore important to distinguish between them because this affects the methods used to fabricate them, the strategies used to stabilize them and the approaches used to design their functional attributes (43,47). An expanded comparison of nanoemulsions and microemulsions is presented in Table IX. Pseudo-ternary phase diagrams are required to optimize SMEDDS, whereas the order of mixing preselected components is not important.…”