In vitro and in vivo release testing of controlled release parenteral microspheres

Date of Completion

January 2005


Health Sciences, Pharmacy




In recent years, the number of approved controlled release parenteral products such as biodegradable microspheres have been increasing in the U.S. market. There is a need to develop in vitro release testing methods for the purpose of standardization of products as well as for good manufacturing practice. Different in vitro release testing methods were investigated for poly(lactic-co-glycolic acid) PLGA microspheres. A modified USP apparatus 4 method was developed to overcome issues such as microsphere aggregation, and loss during release. This method resulted in reliable and reproducible in vitro release profiles that correlated with in vivo release data for dexamethasone from two different microsphere formulations using a rat model. In addition, the versatility of USP apparatus 4 with respect to alteration of flow rate distinguished PLGA formulations with different release characteristics such as diffusion controlled release versus erosion controlled. ^ PLGA microspheres are designed to release drugs over periods of weeks to months in "real-time". Therefore, it is important to develop accelerated release methods that mimic "real-time" drug release. In order to understand drug release kinetics, the microsphere systems were characterized with respect to molecular weight (Mw) change, thermal history, and morphology in "real-time" and under accelerated conditions (elevated temperature, acidic pH and different flow rates). ^ Drug release rates at elevated temperatures (53, 60 and 70°C) for four PLGA formulations with different polymer Mw (5, 25, 28, and 70 kDa) followed Arrhenius kinetics and were able to predict "real-time" (37°C) release rate. Change in polymer Mw with time was used to confirm the mechanism of drug release remained the same in "real time" and at elevated temperature. Mw change followed first order degradation kinetics in both conditions. Elevated temperature accelerated release can be utilized to shorten drug release from months to days, while exhibiting rank order correlation between formulations. However, caution should be taken for formulations where diffusion is the dominant release mechanism since field emission scanning microscopy studies revealed that the morphological changes such as pore closing and geometry changes of the microspheres had an adverse affect of reduction in release. Alteration in flow rate is recommended for diffusion controlled release formulations. ^