F-13

D. M. Saylor¹ , M. K. McDermott¹ , B. J. Dair¹ , C. S. Kim¹ , J. Toy² , D. V. Patwardhan¹ , J. A. Warren³ , ¹OSEL,CDRH,FDA, Rockville, MD, ²ODE,CDRH,FDA, Rockville, MD, ³NIST, Gaithersburg, MD

Background:
A popular method of controlling drug release is to incorporate the drug into a polymer matrix, which acts as a diffusion barrier and thereby slows the rate of drug release. The processing conditions during manufacture affect the composite's structure, but neither that nor the subsequent effects on release rate are well understood.

Methods:
An integrated approach has been taken in an effort to elucidate the inter-relationships between manufacturing conditions, structure, and release kinetics:

1. A predictive theory for the structural evolution of these composite systems has been developed. After specifying thermodynamic and kinetic material parameters, both the structure that forms during manufacture and the release rate of the drug into a target media have been computed.
2. Complementary laboratory investigations have been conducted where model systems are fabricated under different conditions, the composite structures are characterized using standard microscopy techniques, and the release kinetics are measured with a closed loop dissolution apparatus.

Results:
Both the theoretical predictions and experimental measurements indicate that the drug-polymer composite structures are extensively modified by variations in composition and process environment. Furthermore, these modifications have a substantial impact on the release kinetics.

Conclusion:
The rate of drug released from controlled drug delivery systems is extremely sensitive to the structure of the drug-polymer composites that evolves during manufacture. A theoretical and computational framework has been developed to predict the impact of manufacturing conditions on structure and the structure sensitivity of release in these systems. This framework is currently undergoing experimental validation.