International Journal of Pharmaceutics 332 (2007) 140–146 Some non-equilibrium phenomena in the malic acid/water/Polysorbate 81 system Abeer Al Bawab a,∗ , Stig E. Friberg b , Mateus M. Bergamaschi c , Orlando D.H. Santos c a Chemistry Department, Faculty of Science, University of Jordan, P.O. Box 13536, Amman 11942, Jordan b Chemistry Department, University of Virginia, Charlottesville, 22911 VA, USA c Department of Pharmaceutical Science, Faculty of Pharmacy, University of Sao Paulo, Ribeirao Preto, SP, Brazil Received 28 January 2006; received in revised form 10 September 2006; accepted 25 September 2006 Available online 29 September 2006 Abstract Topical formulations undergo radical structural changes after application and the action on the skin is not directly related to the original structure of the formulation. This fact has been well established in the scientific literature. However, and more essential, is the fact that these changes in the formulation structure are not equilibrium ones. Especially so, with the hydroxy acids, which are widely used in cosmetic and dermatological treatment of skin. The article reports the first investigation into the non-equilibrium conditions in a hydroxy acid system. Different phases in the title system, which were not in mutual equilibrium, were brought in contact while avoiding convection. The transfer of substance between them was estimated from the changes in volume of each phase. The results showed, unexpectedly, that the systems were far from equilibrium even after prolonged times in contact. The kinetics of the changes varied to significant degree, from extremely slow, when solid phases were involved to fast for liquid phases. In one case was observed a separated layer, which was not found in the phase diagram under equilibrium conditions. © 2006 Elsevier B.V. All rights reserved. Keywords: Non-equilibrium; Malic acid; Phase diagram; Evaporation; Topical applications 1. Introduction The different association structures in surfactant systems and their equilibria have been extensively investigated and pro- vide thorough information about the subject (Ekwall, 1975; Schramm et al., 2003; Schick, 1992; Holmberg et al., 2002; Shah, 1998; Diamant and Andelman, 2004; Walstra, 1983; Friberg and Neogi, 1989). However, in a large number of indus- trial processes, such as emulsification (Sjoblom, 2001; Julian and Clements, 2004) and extraction (Neogi et al., 1985; Friberg et al., 1986a) the systems are far from equilibrium. In fact, the success of many of these processes entirely depends on the non- equilibrium conditions. ∗ Corresponding author. Tel.: +962 6 777644949; fax: +962 6 5348932. E-mail addresses: drabeer@ju.edu.jo, abeerbawab@yahoo.com (A. Al Bawab). In addition, a large number of commercial products are, per se, non-equilibrium systems, such as emulsions (Larsson, 1994) and most of the vesicle solutions (Simonnet, 1994; Lasic, 1988) to name but two of the best known examples. In spite of this obvious importance, literature in this area is extremely sparse in comparison with the vast information available for equilibrium systems. One fundamental treatment is by Neogi (Friberg et al., 1986b), who analyzed the basis of the appearance of a transient lamellar liquid crystal, which had a decisive influence on an extraction process (Ma et al., 2004). Neogi also reported on the influence by a similar structure in the formation of microemul- sions (Miller and Neogi, 2004). These reports were concerned with liquid systems, but a large number of commercial formula- tions also involve solid compounds and we found a contribution concerning non-equilibrium phenomena in a system containing also a solid to be of interest. It seemed reasonable to expect the solid compound to exert some influence on the transport pro- cesses different from the ones in an entirely liquid system. 0378-5173/$ – see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.ijpharm.2006.09.040