A concise analysis of the effect of temperature and propanediol-1, 2 on Pluronic F127 micellization using isothermal titration microcalorimetry Kawthar Bouchemal * , Florence Agnely, Armand Koffi, Gilles Ponchel Université Paris–Sud 11, UMR CNRS 8612, Physicochimie–Pharmacotechnie–Biopharmacie, Faculté de Pharmacie, 5, Rue J.B. Clément, 92296 Châtenay-Malabry cedex, France article info Article history: Received 2 March 2009 Accepted 29 May 2009 Available online 6 June 2009 Keywords: Pluronic F127 Poloxamer 407 Block copolymer Isothermal titration microcalorimetry Critical micellization concentration Micellization Thermodynamics Propanediol-1,2, dynamics abstract This article aims to explore the possibility of using isothermal titration microcalorimetry (ITC) for the investigation of F127 micellization and to study the effect of temperature and addition of propanediol- 1,2 on F127 micellization behavior. From this work, ITC proved efficient to be used as a tool for the deter- mination of the critical micellization concentration (CMC) and the enthalpy of micellization (DH mic ) of F127, from which the other thermodynamic parameters were calculated (free energy (DG mic ), entropy (DS mic ), and heat capacity of micellization (DC p,mic )). The micellization of F127 was confirmed to be a strongly endothermic process with predominance of hydrophobic interactions (TDS mic > DH mic ) and the correlation of enthalpy and entropy of micelle formation exhibits an excellent linearity. The temperature dependence of F127 micellization was revealed by using ITC, since the CMCs values were, respectively, 0.197, 0.095, 0.085, and 0.079 mM for temperatures 28, 29, 30, and 31 °C. Secondly, by the addition of propanediol-1,2 to the micellization medium containing 1.187 mM of F127, the CMC was shifted to lower values (0.095, 0.081, 0.077, 0.069 and 0.066 mM, respectively, for propanediol-1,2 concentrations of 0%, 1.4%, 2.3%, 2.8%, and 3.7% w/v in the micellization medium). Finally, ITC was used as diagnostic tool with the aim of checking the reproducibility of the experiments independently on the kinetic and the dynamic aspects related to the micelle formation breakup. However, in this work we proved that the use of ITC for the determination of the CMC and thermodynamic parameters associated with F127 micellization is lim- ited to a range of temperatures when sigmoidal curves were obtained. Ó 2009 Elsevier Inc. All rights reserved. 1. Introduction The thermosensitive properties of pharmaceutical formulations based on (ethylene oxide) 97 (propylene oxide) 69 (ethylene oxide) 97 block copolymers known under the generic name of poloxamer 407 and the trade name of Pluronic F127 are of utmost importance in pharmaceutical formulation. Indeed, under appropriate concen- tration conditions in aqueous medium these systems are fluid at room temperature (25 °C) facilitating their administration (for in- stance, via syringes), and in the form of gel above the sol–gel tran- sition temperature promoting prolonged release of active drugs at body temperature (37 °C). Thermosensitive and mucoadhesive gels based on Pluronic F127, hydroxypropylmethylcellulose, and pro- panediol-1,2 were recently developed by Koffi and co-workers [1,2] and appeared to be interesting systems for the rectal admin- istration of quinine. Despite the fact that extensive works have been done concerning the rheological characterization and the evaluation of biological effects of these ternary systems, physico- chemical evaluation of diluted formulations by the investigation of micellization is still lacking. Since micellization represents the very first step in the gelation process, the characterization of the micellization under variable parameters such as temperature and addition of propanediol-1,2 in the micellization medium would represent an original strategy to understand the parameters which govern the thermoreversible property of this system. The process of micellization of Pluronics can be induced by increasing the block copolymer concentration to be above the crit- ical micellization concentration (CMC) (i.e., the concentration at which the micelle formation starts in solution) and/or adjusting the temperature to exceed the critical micellization temperature (CMT) (i.e., the copolymer solution temperature at which the mi- celle formation starts). The CMC of Pluronics is a widely studied phenomenon: it has been determined using various techniques such as surface tension measurements [3], Fourier transformed infrared spectroscopy [4,5], 1 H NMR relaxation studies [6,7], dy- namic light scattering, fluorescence spectroscopy [8], and differen- tial scanning microcalorimetry which allows determination of the enthalpy change related to the micellization process from integra- tion of the heat capacity versus the temperature [9,10]. These experiments also provide the onset temperature for micellization, i.e., the CMT. Nowadays, isothermal titration microcalorimetry (ITC) is the only technique capable of measuring the critical micel- lization concentration and the enthalpy of micellization (DH mic ) of 0021-9797/$ - see front matter Ó 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.jcis.2009.05.075 * Corresponding author. Fax: +33 01 46 61 93 34. E-mail address: kawthar.bouchemal@u-psud.fr (K. Bouchemal). Journal of Colloid and Interface Science 338 (2009) 169–176 Contents lists available at ScienceDirect Journal of Colloid and Interface Science www.elsevier.com/locate/jcis