Atenolol Gastrointestinal Therapeutic System. I. Screening of Formulation Variables

Abstract

Conventional dosage forms are disadvantageous for drugs having short half-lives because of cyclic under- or overdosing and problems of patient compliance. The matrix or reservoir type of controlled-release dosage form provides an alternative. However, bioavailability fluctuations due to gastric pH variations continue to be a problem for many drug candidates. Osmotically controlled drug delivery systems provide a means of eliminating the effect of pH on drug release. However, the literature information is very limited for the effects of formulation variables and other process variables on the release kinetics of drugs from osmotically controlled systems. The objective of this study was to evaluate the factors that influence the release of atenolol, a cardioselective p blocker, from biconvex. bilayered, osmotically controlled tablets coated with a semipermeable membrane of cellulose acetate. Coating was achieved using a Uni-Glatt fluidized-bed coater. Orifices were drilled for drug release and a seven-factor 12-run Plackett-Burman screening technique was employed to evaluate the effects of orifice size, coating level, amounts of sodium chloride, Polyox® N80 and 303, and Carbopol® 934P and 974P on drug release. Response variable was cumulative percent released in 24 hr with constraints on time for 25% and 50% drug release. Factors showing maximum influence on drug release in decreasing order were amounts of Carbopol 934P, coating levels, and orifice size, with the main effect magnitudes of -43.1, 11.56, and 8.17, respectively. Comparative studies for the drug-additive interactions were peeormed using x-ray diffraction and differential scanning calorimetry (DSC). Results of Plackett-Burman screening, x-ray diffraction, and DSC studies are presented.