In Vitro Performance Tests for Controlled Release Parenteral Microsphere Drug Products

Poly(lactide-co-glycolide) (PLGA) microspheres have emerged as one of the most promising controlled release parenteral formulations. The present work addresses the problem of lack of standard in vitro release testing methods for microspheres. This work involves validation of a previously modified USP apparatus 4 method for in vitro release testing of microspheres (for possible compendial adaptation), evaluation of an in vitro-in vivo relationship, and investigation of the application of this method for microspheres encapsulating drugs with different physicochemical properties. In addition, the present work also investigates: the effect of ethanol as an organic phase co-solvent on microsphere characteristics; and the effect of physical ageing on PLGA microsphere performance. ^ Commercial Risperdal® Consta® (risperidone microspheres) were used to validate the USP 4 method and it was shown to be robust and reproducible. A one-to-one linear correlation was observed for both the accelerated and real time release profiles of the risperidone microspheres. The accelerated in vitro release profiles of risperidone microspheres obtained at temperatures above their glass transition temperature correlated well with the in vivo release profile. In the case of protein microspheres it was determined to be important to incorporate surfactants into the release medium to prevent adsorption of the released protein onto the hydrophobic surfaces of the modified USP apparatus 4. This work shows that through the appropriate selection of conditions, USP apparatus 4 method may be used for both quality control purposes and the establishment of an in vitro-in vivo relationship for microspheres. ^ The presence of ethanol as an organic phase co-solvent affected the performance of dexamethasone loaded PLGA microspheres. The changes observed in microsphere physicochemical properties and in vitro release were dependent on many competing factors such as interfacial tension between methylene chloride and water, drug solubility in the organic phase and the polymer phase viscosity. ^ Physical ageing occurred in the microspheres at 25°C as a result of structural relaxation of the polymer chains to achieve a lower equilibrium energy state and this resulted in a slower cumulative percent dexamethasone release from the microspheres. Therefore, physical ageing should be evaluated in addition to the routine stability tests of PLGA microspheres.