International Journal of Pharmaceutics 377 (2009) 142–147 Contents lists available at ScienceDirect International Journal of Pharmaceutics j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / i j p h a r m Rapid communication The universality of low-energy nano-emulsification Nicolas Anton ∗ , Thierry F. Vandamme CNRS 7199, Université de Strasbourg, Faculté de Pharmacie, Laboratoire de Conception et Application de Molécules Bioactives, équipe de Pharmacie Biogalénique, 74 route du 60024 F-67401 Illkirch Cedex, France a r t i c l e i n f o Article history: Received 29 January 2009 Received in revised form 7 May 2009 Accepted 8 May 2009 Available online 18 May 2009 Keywords: Nano-emulsion Emulsification Low-energy Spontaneous emulsification Phase inversion temperature method a b s t r a c t Extensive studies have been done on nano-emulsions and emulsification methods to provide nanometric- scaled templates for the formulation of nanoparticles. The so-called “low-energy” methods are of particular interest as they prevent the potentialdegradation of fragile encapsulated molecules. This work deals with new concepts in nano-emulsification using low-energy methods. Three-model ternary systems,water/nonionic surfactant/oil,were studied and compared.Nano-emulsions were generated using both spontaneous emulsification and the PIT method, so as to study the links between these two nano-emulsification methods.The influence of the composition and formulation variables on the nano-emulsion properties and emulsification procedures were thus investigated. This study pioneers the concept of the universality of low-energy nano-emulsification, proving that all these low-energy meth- ods (i.e. spontaneous emulsification and the phase inversion temperature (PIT) method) are governed by a single unique mechanism. It thus provides a better understanding of low-energy nano-emulsification processes and notably the PIT method, useful in the fields of nanoparticle and nano-pharmaceutic for- mulations. These results are fundamental in establishing experimental procedures for the incorporation of drugs in nano-emulsions. © 2009 Elsevier B.V. All rights reserved. 1. Introduction Nanoparticles, defined as polymeric or lipid particles smaller than 300 nm, are of increasing interest in nano-medicine and nano- pharmaceutics today.They are considered as a tool to help open up a new dimension of treatments,penetrating cells and tissues, targeting diseased zones.However, despite their great potential, nanoparticles are as yet little known and controlled.One way of channelling this potential may be to generate nano-objects with very controlled surface and morphological properties in order to mimic “ideal” natural examples (e.g. viruses), along with a signifi- cant loading in active molecules. This would be intimately related to the control and understanding of their generating processes. Nanoparticles are mainly formulated through the generation of nano-emulsions (Anton et al.,2008) which serve as templates for polymerization, nano-precipitation and lipid nano-crystallization. It therefore follows that understanding the mechanisms of nano- emulsification is of prime interest in all of these processes. Hence the interest of the current study which presents a new point of view on nano-emulsification, disclosing a general and universal mechanism of nano-droplet generation. ∗ Corresponding author. E-mail addresses: nicolas.anton@pharma.u-strasbg.fr (N. Anton), thierry.vandamme@pharma.u-strasbg.fr (T.F. Vandamme). Nano-emulsions consist of a mixture of immiscible liquids, where one of the liquids is dispersed in the form of nanometric- scaled droplets (20–300 nm) into the other one. The generating processes for nano-emulsions are divided into (i) high-energy and (ii) low-energy methods (Anton et al., 2008). High-energy methods involve the use of specific devices such as high-pressure homog- enizers or sonifiers, and only a very low amount (∼0.1%) of the mechanical energy produced is used for emulsification (Tadros et al., 2004). Low-energy methods divert the intrinsic physicochemi- cal properties of the surfactants,co-surfactants and excipients in the formulation, leading to the generation of emulsion droplets in the nanometric range. Owing to the real advantages of low- energy methods in terms of formulation yields, potential industrial scale-up and non-aggressive features (e.g.against encapsulated fragile active molecules),there has been a real research interest in the development of such methods and techniques over the last twenty years. Numerous works lead to “classifying” the low-energy methods into very distinct emulsification procedures, i.e. distinct in the protocols (which depend on the nature of the excipients), but also distinct in the proposed mechanisms for the formation of nano-emulsion droplets. The two commonly reported low-energy nano-emulsification methods are(Anton et al.,2008) the sponta- neous emulsification method and the phase inversion temperature method (PIT method).This study reveals the universality of these low-energy nano-emulsification processes, showing that in fact, all such methods are very close to each other and are governed by a single, common mechanism. 0378-5173/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.ijpharm.2009.05.014