A Staged Approach to Pharmaceutical Dissolution Testing

Software: GastroPlus®


The development of a meaningful dissolution procedure for drug products at different development stages has been a consistent challenge to the pharmaceutical industry.1,2 The objective of dissolution testing, in general, varies during the development stages of a dosage form.3 During preclinical development, dissolution plays an important role of selecting appropriate drug substance and dosage form for the toxicology formulation development to ensure adequate bioavailability. The primary objective of dissolution testing at phase 1 is to characterize the active pharmaceutical ingredient (API), ensure that phase 1 formulation does not release faster than the formulation used in the toxicology assessment, develop first-in-human (FIH) formulations, and establish the preliminary dissolution mechanism. During phases 2 and 3, the objective shifts towards developing an understanding of the impact of key formulation/process parameters on the dissolution profile and an in vitro/in vivo correlation or relationship (IVIVC/IVIVR), if possible. At product registration and beyond, the goal is to identify a quality control (QC) dissolution test method for the product that correlates to the clinical formulations. Dissolution testing is also used by regulatory agencies for granting biowaivers and for post-approval manufacturing changes. The FDA guidance for waivers of in vivo bioavailability and bioequivalence studies (“Waiver of in vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System”) employs dissolution testing to demonstrate rapid dissolution of immediate-release solid oral dosage forms so that a biowaiver can be granted.4 Continual evolution of these objectives during the drug product life cycle may require different concentrations and, therefore, require changes in the analytical finish.