Evaluation of “External” Predictability of an In Vitro–In Vivo Correlation for an Extended‐Release Formulation Containing Metoprolol Tartrate

Abstract

The purpose of this study was to examine the external predictability of an in vitro–in vivo correlation (IVIVC) for a metoprolol hydrophilic matrix extended‐release formulation, with an acceptable internal predictability, in the presence of a range of formulation/manufacturing changes. In addition, this report evaluated the predictability of the IVIVC for another formulation of metoprolol tartrate differing in its release mechanism. Study 1 examined the scale up of a matrix extended‐release tablet from a 3‐kg small batch (I) to a 50‐kg large batch (II). The second study examined the influence of scale and processing changes [3‐kg small batch with fluid bed granulation and drying (III); 80‐kg large batch with high shear granulation and microwave drying (IV), and a formulation with an alternate release mechanism formulated as a multiparticulate capsule (V)]. In vitro dissolution of all formulations (I–V) was conducted with a USP apparatus I at pH 6.8 and 150 rpm. Subjects received the metoprolol formulations, and serial blood samples were collected over 48 h and analyzed by a validated HPLC assay using fluorescence detection. A previously developed IVIVC was used to predict plasma profiles. Prediction errors (PE) were <10% for Cmax and area under the curve (AUC) of concentration versus time for I, II, and IV. The Cmax for III was slightly underestimated (11.7%); however, the PE of the AUC was <10%. Formulation V displayed a PE for Cmax > 20% and an AUC within 5% of observed values. The low PEs for Cmax and AUC observed for I–IV strongly suggest that the metoprolol IVIVC is externally valid, predictive of alternate processing methods (IV), scale‐up (II, III), and allows the in vitro dissolution data to be used as a surrogate for validation studies. However, the lack of predictability for V supports the contention that IVIVCs are formulation specific. © 2000 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 89: 1354–1361, 2000