Monitoring release of ketoprofen enantiomers from biodegradable poly(d,l-lactide-co-glycolide) injectable implants

A stereoselective reversed-phase HPLC assay was developed that could simultaneously quantify S-(+) and R-(−) enantiomers of ketoprofen in release samples. Racemic ketoprofen (rac-KET) and its S-(+) enantiomer (S-(+)-KET) were dissolved in an injectable viscous polymer solution consisting of the biodegradable poly(d,l-lactide-co-glycolide, 70:30) (d,l-PLG) and a solvent, N-methyl-2-pyrrolidone (NMP). Once injected into an aqueous environment, the polymeric mixture solidified into a solid implant due to the leaching of NMP. In vitro release studies show that such implants with ketoprofen can provide sustained release of the drug lasting about three months in a pH 7.4 release medium. Moreover, a preferential faster S-(+)-KET release over R-(−)-KET was observed for the implants containing 4%, 7%, and 10% of racemic ketoprofen in the neutral pH 7.4 release medium. Stereoselective release was minimal in the first 42 days in vitro but became very pronounced at later time points. When S-(+)-KET was incorporated into the polymeric mixture, its release was also faster than that of the racemic ketoprofen, confirming the stereoselective release of ketoprofen from the d,l-PLG implants. The observed stereoselective release of KET at pH 7.4 was most likely produced by chiral interactions between KET enantiomers and transiently produced d-lactic acid or l-lactic acid rich domains within the implants during d,l-PLG degradation. However, such stereoselective release was not observed in pH 10.0 release medium, probably due to a much faster and homogeneous polymer degradation. The study suggests possible stereoselective release of racemic drugs from d,l-PLG microspheres and implants in vivo.