Abstract

OPTIMIZATION OF FLUIDIZED-BED PROCESSING PARAMETERS FOR PREPARING TOPIRAMATE EXTENDED-RELEASE CAPSULES BY CHEMOMETRIC MODELING

Yong Li*, Bill Wei, Weiyong Li, Changyuan Yu, Xinguo Wang and Herling Uang

ABSTRACT

Topiramate is a new class of anti-epileptic drug, which is effective for various types of epilepsy, is well tolerated and has a good safety profile. Supernus Pharmaceuticals successfully developed a product of extended-release capsules and subsequently received approval in the United States. However, the product consists of pellets with different release behaviors, which are prepared separately and finally mixed to fill the capsule to achieve extended drug release. This article discusses a new and simpler formulation of topiramate extended-release capsules. In the process development, the authors created chemometric models to study the two fluidized-bed coating steps. These models were used to elucidate the relationships between formulation/process variables and coating quality, and computer simulations were used to optimize the ranges of key process parameters. To verify validity of the chemometric models and the optimized coating steps, three batches of the product were prepared and their dissolution test conducted at different pHs. The new product showed very similar drug-release characteristics to that of the Supernus product. The adoption of chemometric methods can speed up process development, ensure stability of the drug production process and reduce R&D costs.

Keywords: Partial least squares regression, Computer simulation, Topiramate, Fluidized bed, Coating.