Design and manufacture of a zero-order sustained-release pellet dosage form through nonuniform drug distribution in a diffusional matrix.

A theoretical basis is presented for the design of dosage forms containing a drug which is initially distributed throughout a noneroding diffusional matrix in a nonuniform manner, for the purpose of achieving zero-order release. Modeling of these dosage forms is based on Higuchi's square root of time diffusional model. Derivations of theoretical drug release profiles for both flat slab and spherical geometry are included. Pellets were prepared utilizing this nonuniform distribution concept using fluid bed suspension layering technology. A gradient pumping system used in conjunction with a specially fabricated miniature fluid bed apparatus was utilized to prepare pellets containing drug nonuniformly dispersed. Actual drug release profiles were obtained for pellets containing drug distributed in the traditional uniform manner and the nonuniform manner described above. Nonuniform distribution of drug in a noneroding diffusional matrix, in theory and practice, is shown to linearize dissolution profiles.