Oral bioavailability of drugs and drug formulations: The interplay of dissolution, colloidal phases, and permeation

Ann-Christin Jacobsen

Research output: ThesisPh.D. thesis


Biopharmaceutical characterisation of enabling formulations is challenging. Upon ingestion
of an enabling formulation, the drug is often present in various states: solid (i.e. crystalline or
amorphous), dissolved (i.e. eventually supersaturated) and associated with solubilizing
constituents (e.g. colloidal phases such as micelles). How the different states of drug present
in the gastrointestinal tract contribute to overall drug absorption (i.e. oral bioavailability) is
often not well understood. It has been demonstrated that the in vivo performance of
supersaturating enabling formulations can be predicted more accurately when testing
dissolution in an absorptive environment. This experimental design is closer to the in vivo
situation where dissolution and permeation happen concurrently. Unfortunately, the
throughput of these coupled dissolution/permeation approaches is often low due to e.g. the
nature of the permeation barrier and the design of the device.
The aim of this thesis was to explore if coupled dissolution/permeation approaches with
higher throughput could be developed. Furthermore, this thesis strived to gain a better
understanding of the interplay of dissolution, colloidal phases, and permeation leading to oral
absorption. For this purpose, dissolution/permeation approaches were regarded as useful.
Together with an industry partner, a 96-well plate with two compartments and comprising
the Permeapad® barrier was developed – the starting point to obtain the desired throughput
profile. Permeability studies using 14 model compounds followed by comparison to various
measures for oral absorption (i.e. Fa and permeability assays) showed the potential of this
industrially produced tool. A protocol for dissolution/permeation screening in 96-well format
was developed using a tadalafil ASD as example formulation and by evaluating different
experimental parameters. As compared to traditional dissolution testing, the novel protocol
predicted the formulations’ in vivo performance more accurately. To study the interplay of
dissolution, colloidal phases and permeation in detail, solid phospholipid dispersions were
prepared. Here, (amorphous) celecoxib was embedded in a phospholipid matrix, which upon
dispersion formed solubilizing colloids. For the first time, two phospholipids, monoacyl and
diacyl phospholipid forming different colloids, were systematically compared in an
(apparent) solubility, a dissolution/permeation, and an AF4-MALLS study. Interestingly,
monoacyl and diacyl formulations differed in terms of solubility but were equal in terms of
dissolution/permeation behaviour. To relate the in vitro findings to the in vivo scenario,
celecoxib absorption from monoacyl and diacyl formulations was studied in rats. In
conclusion, both the in vitro dissolution/permeation study and the in vivo study showed:
Inducing and maintaining supersaturation governs oral absorption whereas the
solubilization capacity and the morphology of the colloidal phases seem to be less important.
Original languageEnglish
Awarding Institution
  • University of Southern Denmark
  • Bauer-Brandl, Annette, Principal supervisor
  • Brandl, Martin, Co-supervisor
Publication statusPublished - Nov 2020


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