Maturation of a ketoprofen/β-cyclodextrin mixture with supercritical carbon dioxide

This work studies the maturation process of an association complex between an active compound, ketoprofen (KP) and a β-cyclodextrin (CD) with supercritical carbon dioxide (SC-CO2). The process involves putting these two compounds into contact with a certain quantity of water, over a certain duration, to obtain the complex. We have studied the phenomena involved and the influence of several operating parameters on the complexation rate. The results enable us to suggest explanations for the phenomena involved in inclusion formation. An increase in the parameters related to the process: pressure, temperature, maturation period, agitation and density of SC-CO2 resulted in an increase in the association rate of KP with CD in all cases. The water added at the end of the mixing procedure allowed a surface solubilization of CD where a ripening phenomenon can occur, but it is also a destabilizing agent for the water already adsorbed on the CD. The added water then favours an evolution towards a more stable energy state by enhancing the emptying of the CD cavities, and being replaced by KP. The mass ratio of the SC-CO2/mixture had an effect on association, as the use of great volumes of CO2 caused dilution of KP and was deleterious to the complexation rate. It was also found that the method of mixture preparation influenced the formation of the complex: adding water before KP onto CD inhibited complexation. The stoichiometry of complexation was found to be one molecule of KP with two molecules of CD. With control of both the operating conditions (pressure, temperature, maturation period, agitation and density of SC-CO2) and the preparation of the mixing, this process leads to high percentages of complexation without the use of organic solvent.