METHODS TO COMPARE DISSOLUTION PROFILES AND A RATIONALE FOR WIDE DISSOLUTION SPECIFICATIONS FOR METOPROLOL TARTRATE TABLETS

The objectives of this work were to apply several profile comparison a pproaches to dissolution data of four different but bioequivalent meto prolol tartrate tablet formulations to (1) identify the advantages and disadvantages of each approach, (2) quantify the metric for comparing dissolution profiles of each method, (3) determine metric limits that are consistent with the observed bioequivalence, and (4) rationalize the observed metric limits with respect to the role of dissolution in overall metoprolol absorption. Dissolution was performed by the USP mo nograph method on four formulations of metoprolol tartrate tablets (Lo pressor plus fast, medium, and slow dissolving test formulations). Thr ee general approaches to compare dissolution profiles were examined; t hey were ANOVA-based, model-independent, and model-dependent approache s, It is concluded that model-independent approaches and several model -dependent approaches yielded numerical results that can serve as obje ctive and quantitative metrics for comparing entire dissolution profil es of the four metoprolol tartrate formulations. However, these method s presented complications. Some metrics were dependent on the length o f the dissolution profile and the sampling scheme. Results from the pa irwise procedures also depended on the pairing assignment of individua l profiles. In spite of complications, these methods suggested wide di ssolution specification limits. Wide dissolution specifications were r ationalized through an analysis of in vitro-in vivo relationships, whi ch indicated metoprolol dissolution from these formulations was not th e rate-limiting step; hence, a range of dissolution profiles can be ex pected to yield equivalent plasma profiles.