A contribution to overcoming the problem of residual solvents in biodegradable microspheres prepared by coacervation

Abstract

The influence of manufacturing variables and different drying conditions on the amount of residual solvents and on other quality characteristics of biodegradable PLA- and PLGA-microspheres was investigated. Empty and BSA-loaded microspheres were prepared by an organic phase separation method using either dichloromethane (DCM) or ethyl acetate (EtAc) as polymer solvents, silicone oil as the coacervating agent, and either octamethylcyclotetrasiloxane (OMCTS) or hexane as the hardening agents. Microspheres were subjected to different drying conditions varying in time (24 h, 72 h), temperature (25 °C, 40 °C) and pressure (5 mbar, 0.05 mbar). Residual solvents were assayed by gas chromatography. Silicone oil was determined by 'H-NMR and FT-IR. Depending on the type and molecular weight of polymer, substantial amounts of solvents and non-solvents remained in the spheres, even after prolonged drying at reduced pressure. The lowest amount of residual solvents were obtained by raising the drying temperature near the T g of the polymer. This process was more effective for DCM (< 100 ppm, USP-limit : 500 ppm) than for EtAc (2.1%, no USP-specification). In contrast, the amount of residual hardening agent (0.5-5% OMCTS or 2-5% hexane) was not influenced by the drying conditions but primarily by the affinity between solvent, polymer and hardening compound. Vacuum-drying influenced the morphology of the BSA-loaded microparticles, but not of the unloaded microspheres. No correlation was found, however, between the drying conditions and the initial release of protein. The study showed that the particular components used for coacervation and the drying conditions both exert a crucial effect on the organic volatile impurities in the final products.