PROCESS VARIABLE IMPLICATIONS FOR RESIDUAL SOLVENT REMOVAL AND POLYMER MORPHOLOGY IN THE FORMATION OF GENTAMICIN-LOADED POLY(L-LACTIDE) MICROPARTICLES

Purpose. The purpose was to determine the influence of process paramet ers in the precipitation with a compressed antisolvent (PCA) process o n the morphology and residual dichloromethane (DCM) levels in gentamyc in-loaded PLA microparticles. Methods. The three variables studied wer e the rate of CO2 co-flowed during the polymer and drug co-precipitati on, the post-precipitation pure CO2 flush rate, and the post-precipita tion CO2 flush volume. Residual DCM levels were determined from headsp ace gas chromatography - mass spectroscopy (GC-MS) with single ion mon itoring. Xray diffraction (XRD) and differential scanning calorimetry (DSC) were used to estimate the crystallinity within microparticles. D CM was extracted from drug-loaded microparticles by both supercritical CO2 extraction and vacuum drying for up to two days to determine a lo wer limit for solvent removal. Results. Increasing either the post-pre cipitation CO2 flow rate or flush volume resulted in lower residual DC M levels in the microparticle. The CO2 co-flow rate showed an opposite trend. Increasing its value resulted in a higher DCM value after prec ipitation. XRD and DSC analysis on these samples suggest that those pr oduced at lower CO2 co-flow rates have a higher degree of crystallinit y, which increases the diffusivity of DCM through the polymer matrix. Finally. samples subjected to extended (48 hr) CO2 extraction resulted in DCM levels on the order of one to three ppm. Conclusions. Specific PCA process conditions during microparticle formation have a strong i nfluence on the residual solvent levels within the microparticles. Pol ymer morphology affects the diffusivity of solvent through the polymer matrix, which in turn determines the solvent removal rates.