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The study explores the enabling role of near-critical CO2 as a reversible plasticizer in the high pressure homogenization of polymer particles, aiming at their comminution as well as at the formation of drug–polymer composites. First, the effect of near-critical CO2 on the homogenization of aqueous suspensions of poly lactic-co-glycolic acid (PLGA) was investigated. Applying a pressure drop of 900 bar and up to 150 passes across the homogenizer, it was found that particles processed in the presence of CO2 were generally of microspherical morphology and at all times significantly smaller than those obtained in the absence of a plasticizer. The smallest particles, exhibiting a median x50 of 1.3 μm, were obtained by adding a small quantity of ethyl acetate, which exerts on PLGA an additional plasticizing effect during the homogenization step. Further, the study concerns the possibility of forming drug–polymer composites through simultaneous high pressure homogenization of the two relevant solids, and particularly the effect of near-critical CO2 on this process. Therefore, PLGA was homogenized together with crystalline S-ketoprofen (S-KET), a non-steroidal anti-inflammatory drug, at a drug to polymer ratio of 1:10, a pressure drop of 900 bar and up to 150 passes across the homogenizer. When the process was carried out in the presence of CO2, an impregnation efficiency of 91% has been reached, corresponding to 8.3 wt.% of S-KET in PLGA; moreover, composite particles were of microspherical morphology and significantly smaller than those obtained in the absence of CO2. The formation of drug–polymer composites through simultaneous homogenization of the two materials is thus greatly enhanced by the presence of CO2, which increases the efficiency for both homogenization and impregnation.