Selection of In Vivo Predictive Dissolution Media Using Drug Substance and Physiological Properties

ABSTRACTThe rate and extent of drug dissolution in the gastrointestinal (GI) tract are highly dependent upon drug physicochemical properties and GI fluid properties. Biorelevant dissolution media (BDM), which aim to facilitatein vitro prediction ofin vivo dissolution performance, have evolved with our understanding of GI physiology. However, BDM with a variety of properties and compositions are available, making the choice of dissolution medium challenging. In this tutorial, we describe a simple and quantitative methodology for selecting practical, yet physiologically relevant BDM representative of fasted humans for evaluating dissolution of immediate release formulations. Specifically, this methodology describes selection of pH, buffer species, and concentration and evaluates the importance of including bile salts and phospholipids in the BDM based upon drug substance logD, pKa, and intrinsic solubility. The methodology is based upon a mechanistic understanding of how three main factors affect dissolution, including (1) drug ionization at gastrointestinal pH, (2) alteration of surface pH by charged drug species, and (3) drug solubilization in mixed lipidic aggregates comprising bile salts and phospholipids. Assessment of this methodology through testing and comparison with literature reports showed that the recommendations correctly identified when a biorelevant buffer capacity or the addition of bile salts and phospholipids to the medium would appreciably change the drug di...
Source: The AAPS Journal - Category: Drugs & Pharmacology Source Type: research