Disintegration and dissolution of IR solid dosage forms in fed state media and influence of tablet excipients

The ICH M13 Bioequivalence Guideline Part A has finalized the commenting period in May 2023 and discussions on the necessity of demonstrating BE in fasting and fed states is still ongoing. In particular there are different opinions whether fasting and fed state studies are necessary even for IR formulations without complex galenics. While it seems undisputed that BE studies under fed and fasted conditions can be justified for complex formulations (e.g. solid solutions/dispersions, self-emulsifying drug delivery systems), the role of excipients in “simple” formulations in fasted and fed state media is still unclear following studies by Radwan et al , Zaheer et al , Cvijic et al and others. Recent progress has been made in establishing dissolution media with enhanced viscosity simulating the fed state and dissolution equipment which will ensure proper mixing of the viscous chyme and the dissolved drug. Furthermore, there is evidence that low soluble excipients in the tablet matrix (e.g. microcrystalline cellulose, dicalcium phosphate, starch) present higher risk of severely delayed disintegration and dissolution in fed state media whereas in normal viscosity media these are behaving as rapidly dissolving tablets. This indicates that food effects cannot be excluded in fed states in case high risk excipients are present in the new versus the comparator formulation which may not be detected in fasted state studies. These in vitro observations necessitate in vivo pharmacokinetic studies to validate the predictability of the food effect by the novel in vitro tools. Thereafter, in vivo food effect studies may be replaced by in vitro dissolution studies demonstrating the similarity of both formulations under fasted and fed state conditions, thus pointing out to a new class of biowaiver opportunities.