International Journal of Pharmaceutics 344 (2007) 44–52 Nano-emulsions and nanocapsules by the PIT method: An investigation on the role of the temperature cycling on the emulsion phase inversion Nicolas Anton a , Pascal Gayet a , Jean-Pierre Benoit a,b , Patrick Saulnier a,∗ a University of Angers, Inserm U646, Ing´ enierie de la vectorisation particulaire, 10 rue A. Boquel, F-49100 Angers, France b ´ Ecole pratique des hautes ´ etudes (EPHE), 12 rue Cuvier, F-75005 Paris, France Received 26 January 2007; received in revised form 16 April 2007; accepted 25 April 2007 Available online 6 May 2007 Abstract This paper focuses on the phenomenological understanding of temperature cycling process, applied to the phase inversion temperature (PIT) method. The role of this particular thermal treatment on emulsions phase inversion, as well as its ability to generate nano-emulsions have been investigated. In order to propose a general study, we have based our investigations on a given formulation of nano-emulsions classically proposed in the literature [Heurtault, B., Saulnier, P., Pech, B., Proust, J. E., Benoit, J.P., 2002. A novel phase inversion-based process for the preparation of lipid nanocarriers. Pharm. Res. 19, 875; Lamprecht, A., Bouligand, Y, Benoit, J.P., 2002. New lipid nanocapsules exhibit sustained release properties for amiodarone. J. Control. Release 84, 59–68], using a polyethoxylated model nonionic surfactant, a polyoxyehtylene-660-12-hydroxy stearate, stabilizing the emulsion composed of caprilic triglycerides (triglycerides medium chains), salt water (and also phospholipidic amphiphiles neutral for the formulation). Characterization of nano-emulsions was performed by dynamic light scattering (DLS) which provides the hydrodynamic diameter, but also the polydispersity index (PDI), as a fundamental criteria to judge the quality of the dispersion. Another aspect of the characterization was done following the emulsion inversion and structure by electrical conductivity through the temperature scan. Overall, the role such a temperature cycling process on the formulation of nano-emulsions appears to be relatively important, and globally enhanced as the surfactant concentration is lowered. Actually, both the hydrodynamic diameter and the PDI decrease as a function of the number and temperature cycles up to stabilize a steady state. Eventually, such a cycling process allows the generation of nano-emulsions in ranges of compositions largely expanded when compared with the classical PIT method. These general and interesting trends emerge from the results, are discussed and essentially explained by regarding the behavior of the nonionic surfactants towards the water/oil interface, linking partitioning coefficients, temperature variation, and surfactant water/oil interfacial concentration. In that way, this paper proposes new insights into the phenomena governing the PIT method, by originally investigating the temperature cycling process. © 2007 Elsevier B.V. All rights reserved. Keywords: Nano-emulsion; PIT method; Emulsion; Temperature cycling; Nonionic 1. Introduction Nanometric-sized emulsions until 300 nm, so-called nano- emulsions or miniemulsions, were widely studied for their numerous potential applications. Nano-emulsions are trans- parent or translucent systems, kinetically stable (in contrast with microemulsions which show a thermodynamic equilibrium between components present in the different phases). These nano-emulsions are also characterized by a great stability in ∗ Corresponding author. E-mail addresses: nicolas.anton@univ-angers.fr (N. Anton), p gayet@hotmail.com (P. Gayet), jean-pierre.benoit@univ-angers.fr (J.-P. Benoit), patrick.saulnier@univ-angers.fr (P. Saulnier). suspension due to their droplet sizes, i.e. the fact that the prin- cipal cause of instability is due to Ostwald ripening (Taylor, 1998). It is only in recent years that this subject has seen a real explosion in research activity partly due to cosmetic and pharma- ceutical applications that have initiated the formulation of novel systems generating nanoparticles. Their property of immune privilege has generated considerable interest. Another impor- tant advantage of nano-emulsions comes from the fact that their high stability in suspension is fundamental for many industrial applications. Processes used to generate nano-emulsions can be separated in two fundamentally different families: the first one gathers high-energy emulsification methods (utilizing either high pres- sure homogenizers or ultrasound generators) and can be in 0378-5173/$ – see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.ijpharm.2007.04.027