The development of an extended-release metoprolol tartrate dosage form, its in vitro and in vivo evaluation and the applications of in vitro-in vivo correlation across release mechanisms as a predictor of in vivo performance

Abstract

In the past four years three guidances have been prepared for the pharmaceutical industry which dealt with different aspects of extended-release dosage forms. This dissertation focused on one main issue from each of the three guidances. The first issue addressed pharmaceutical equivalence requirements. The second issue examined how multiple changes in formulation and process variables affect in vitro dissolution test result. The third issue concentrated on in vitro-in vivo correlation (IVIVC) as a predictor of in vivo performance across release mechanisms. A metoprolol tartrate extended-release capsule formulation was developed using fluid bed multiprocessor equipment with Wurster insert. Sugar spheres were drug-layered with metoprolol tartrate, seal-coated with Opadry (hydroxypropyl methylcellulose) and film-coated with Surelease (ethylcellulose). This dosage form was compared to a reference metoprolol tartrate matrix tablet dosage form which was formulated using Methocel K100LV (hydrodroxypropyl methylcellulose) as a hydrophilic polymer to retard the release. The mechanisms of release between both dosage forms differ. In the case of the tablet (reference) product, release is a function of the square root of time and the release rate can be controlled by the tablet porosity, addition of soluble solids, and the ratio of drug to carrier. The mechanism and kinetics of drug delivery from the capsule (test) formulation depend on the nature of the film and can be controlled by film porosity and thickness. For insoluble membranes made of ethylcellulose, drug release depends primarily on diffusion and partitioning of the drug into the membrane. Dissolution tests using different media, agitation speeds and methods were performed on both formulations to determine how the differences in dosage forms in terms of appearance or type (multiparticulate vs single unit) and release mechanism affect in vitro release. An in vitro-in vivo correlation (IVIVC) between plasma concentration and dissolution rate for matrix tablet formulation of the same drug was used to predict the in vivo performance of the capsule formulation. A clinical study was conducted using the capsule formulation and the bioavailability parameters derived from this study were compared to those predicted from the matrix tablet IVIVC. Both formulations released drug similarily under different dissolution testing conditions (f2>75). While the extent of release from both formulations was similar in vivo, the rate of release was not. This finding was also reflected in the predictions made using the matrix tablet IVIVC. The area under the curve (AUC) was adequately predicted (error<3%) whereas, the maximum concentration (Cmax) which is a bioavailability parameter that reflects rate in addition to extent of absorption was not well predicted(error>20%). The results demonstrate: (1) the f2 criteria used to determine in vitro profile similarity between formulations may not be suitable when the dosage forms being compared differ in release mechanisms, and/or (2) the IVIVC is formulation and mechanism dependent. The differences found in the in vivo absorption rates of these two formulations reflect differences in the dynamics of stomach emptying and intestinal transport between a multiparticulate dosage form compared to a monolithic matrix tablet dosage form.