Introduction
Rapid and consistent in-vivo drug dissolution is critical for drug absorption. In-vitro dissolutions tests are used to predict in-vivo disintegration and dissolution properties of drug products. The in-vitro disintegration and dissolution times of tablets and capsules can vary signi cantly based on their composition and processing. Though small differences in-vitro dissolution are not expected to result in signi cant in-vivo performance differences, the slight in-vitro dissolution delay observed by over-encapsulation for double blind clinical trials, as well as switching from gelatin to HPMC capsules often raises concerns on the potential impact on in-vivo bioavailability. While it is accepted that the in-vitro dissolution delay of about 5 minutes caused by over-encapsulation with gelatin capsules of immediate release (IR) tablets or powder formulation does not lead to non-bioequivalence, no data on bioequivalence exist for over-encapsulation with an HPMC capsule having a dissolution lag time of around 10 minutes. To assess the potential impact, a comparative investigation was performed using in-vitro dissolution, PK simulation and human bioequivalence comparing an IR xed dose combination compressed caplet containing three different rapidly-absorbed drugs over- encapsulated with gelatin capsules and the same caplet over-encapsulated with HPMC capsules made by a thermo-gelation process. Two piece hard gelatin capsules (HGC) have been used to deliver medicines and nutritional supplements for over 80 years [Colton, 1931]. These types of HGCs are well-described in pharmacopoeial monographs and in the literature and their in-vitro and in-vivo behavior has been extensively characterized. Due to their reliable IR performance, HGCs are widely used for a variety of formulations and delivery applications [Stegemann 2011, Cole et al., 2008, Deepthi & Murthy, 2015].
