Role of solvent/non-solvent ratio on microsphere formation using the solvent removal method

Abstract

The importance of good solvent concentration in the non-solvent mixture and the non-solvent viscosity on the ability to form microspheres using solvent removal process was investigated. The higher the viscosity of the polymer solutions, the higher the concentration of good solvent needed in the non-solvent mixture to produce microspheres. This finding was due to faster precipitation of the polymer phase. Also, the addition of a model drug, fluorescein isothiocyanate conjugated-labelled bovine serum albumin, to the polymer solution (10% poly-L-lactic acid:poly(fumaric-co-sebacic) anhydride in methylene chloride) resulted in an overall lower polymer solution viscosity (15.5 cP with fluorescein isothiocyanate conjugated-labelled bovine serum albumin as compared with 18.25 cP for blank polymer at 25°C). Additionally, the effect of good solvent concentration on non-solvent viscosity was evaluated, and the viscosity decreased as the concentration of good solvent increased. The effect of good solvent concentration on the non-solvent mixture on sphere formation was of great importance. Microspheres would not form when the good polymer solvent (methylene chloride) in the non-solvent phase was too low (below 175 ml for poly-L-lactic acid or 150 ml for poly(D,L-lactid-co-glycolid)) or was replaced by another good solvent such as ethyl acetate, even though the same viscosity was achieved. It was shown that the concentration of the good solvent in the non-solvent mixture was more of a controlling factor than the viscosity of the non-solvent mixture in microsphere formation and the findings support the conclusion that diffusion is the main controlling parameter in solvent removal.