Zero-order release through nonuniform drug distribution in a noneroding diffusional matrix: Theoretical design and actual manufacture

Abstract

The theoretical design and actual manufacture of a non-eroding matrix pellet dosage form was undertaken. Non-uniform drug distribution in a non-eroding matrix can be used as a technique to achieve zero-order release. Flat slab and spherical geometry were examined through the development of a mathematical model to verify that it is theoretically possible to achieve zero-order release. Traditional non-eroding matrices, which contain drug uniformly distributed, do not yield zero-order release due to a constantly increasing barrier thickness which develops as drug diffuses from the matrix. Non-uniform drug distribution in a porous non-eroding matrix, in which drug is more concentrated in deeper matrix layers, creates an increasing depletion zone porosity as drug is leached from the matrix. This increasing porosity compensates for the increasing barrier thickness to achieve constant rate release. A common pelletization technique was employed to manufacture pellets. Previous investigations of this approach are few and have never combined a theoretical approach with a practical manufacturing process. An automated modified suspension layering technique was developed to create pellets containing drug non-uniformly distributed. A gradient pumping system used in conjunction with a specially fabricated Wurster column was used to produce these pellets. To examine the feasibility of this process, an investigation of the behavior of a water soluble drug, chlorpheniramine maleate, and a water insoluble drug, haloperidol, was undertaken. The model drugs and non-eroding matrices were characterized and actual release profiles were compared to theoretical profiles. In the case of the water soluble drug, an alternate release mechanism appears to predominate and the system does not behave as predicted by theory. In the case of the water insoluble drug the model fits well. A slight burst of drug is observed and is due to an initial porosity which exists in the matrix. The differing performance of these drugs appears to be due to their physico-chemical character. The water insoluble drug conforms to the assumptions and conditions of the model and demonstrates that non-uniform drug distribution in theory and actuality can be used to achieve zero-order release.