Solubility of Ketoprofen in colloidal PLGA

The successful design and development of pharmaceutical drug-polymer composites requires detailed information about the phase behavior of the drug-polymer binary system. This study presents an extended investigation of the phase equilibrium established between the chiral anti-inflammatory drug Ketoprofen (KET) and the bio-compatible and biodegradable polymer poly(lactic-co-glycolic) acid 5050 (PLGA). Equilibration experiments were carried out in aqueous suspensions of KET crystals together with PLGA in the form of spherical amorphous nanoparticles obtained by supercritical fluid extraction of emulsions (SFEE). The influence of temperature was studied in the range between 0°C and 50°C, while the effect of KET chirality was investigated by using two different crystalline forms of KET, namely enantiopure S-KET and a racemic compound, RS-KET, in equilibration experiments. It was found that the level of KET established in PLGA at equilibrium increases with temperature, e.g. from 6.9 wt.% at 20°C to 25.8 wt.% at 40°C for the case of S-KET. At each temperature level, the solubility of KET in PLGA was lower for equilibration with RS-KET, significantly higher for equilibration with S-KET, and the highest for simultaneous equilibration with both crystalline species. Experimental solubility data of KET in PLGA were also described in a model based on the Sanchez-Lacombe equation of state. For experiments carried out at 10°C or below, an equilibrium state could not be reached even after a prolonged equilibration period, presumably because the polymer phase had undergone a transition into the glassy state. For this temperature range, where an experimental equilibration is not any more possible, the model may be used to estimate the solubility of KET in PLGA by extrapolation.