Comparison of Drug Release From Metoprolol Modified Release Dosage Forms in Single Buffer versus a pH-Gradient Dissolution Test

Introduction Metoprolol is a cardioselective beta blocker that has been classified as a class I substance according to the Biopharmaceutics Classification Scheme BCS [1], meaning that it is highly soluble and highly permeable. The drug is readily and completely absorbed throughout the whole intestinal tract [2-4] but is subject to extensive firstpass metabolism resulting in incomplete bioavailability (about 50%). After a single oral dose,peak plasma concentrations occur after about 1-2 hours. The drug is eliminated within 3 to 4 hours,which,depending on therapeutic intention,makes it necessary to administer simple formulations of metoprolol up to 4 times daily [5]. Based on these properties and the well-defined relationship between the betablocking effect and plasma drug concentration [6], metoprolol lends itself to an extended-release (ER) formulation. Metoprolol ER formulations smooth out peaks and valleys in the plasma levels and enable less frequent dosing. Dosing intervals are typically reduced to once or twice a day. Several types of metoprolol ER formulations are available internationally at the time of writing.“Conventional”ER formulations of metoprolol are single-unit,coated dosage forms (tablets) containing metoprolol tartrate,which is highly soluble. These formulations have been the standard medication for hypertension and angina pectoris in Germany for many years. In 1990 Belok-Zok®,a different type of ER formulation,was released by AstraZeneca. This formulation consists of a tablet that rapidly disintegrates,releasing micropellets with a diameter of ~0.5 mm that contain metoprolol succinate. Like the tartrate,metoprolol succinate is highly soluble. Each of the pellets is designed to act as a diffusion cell that delivers the drug at a relatively constant rate,essentially relatively independent of physiological variations within the GI tract [6]. In 2001 an alternative zero order kinetics (ZOK) formulation was approved for the German market. This consists of a matrix tablet in which metoprolol tartrate is embedded. Hence,to date,there are basically three different types of ER metoprolol formulations available that are registered for equal therapeutic objectives on the German market. Within the last years,especially in Germany,substitution of innovator products coming off patent by generics has become common practice. However, if substitution is only based on dosage strength without recognizing differences in formulation that could affect rate and/or extent of release, this could place the patient at unnecessary risk. Based on these considerations,the present study was undertaken to assess the interchangeability of the various ER metoprolol tartrate and succinate dosage forms on the basis of their in vitro dissolution characteristics. Recent pharmacopoeial test methods for metoprolol ER formulations prescribe the use of USP Apparatus 1 or 2 and simple dissolution media like SGFsp pH 1.2 or phosphate buffer pH 6.8 [7]. Such methods may be useful for quality control purposes in terms of batch-to-batch conformity. However,they do not comprehensively reflect conditions to which a dosage form moving through the human GI tract will be exposed and therefore cannot be used to predict drug release during the course of GI passage. In view of the properties of metoprolol and the release mechanisms of the various formulations on the market, it was deemed both necessary and sufficient to establish a simple pH-gradient method with elements of standard methods such as these described in the USP,but additionally reflecting the changing pH conditions as the dosage form proceeds through the human GI tract, in order to predict any differences in in vivo performance.