title: Characterising Drug Release from Immediate-Release Formulations of a Poorly Soluble Compound, Basmisanil, Through Absorption Modelling and Dissolution Testing.
abstract: The study aimed to characterise the mechanism of release and absorption of Basmisanil, a biopharmaceutics classification system (BCS) class 2 compound, from immediate-release formulations via mechanistic absorption modelling, dissolution testing, and Raman imaging. An oral absorption model was developed in GastroPlus® and verified with single-dose pharmacokinetic data in humans. The properties and drug release behaviour of different oral Basmisanil formulations were characterised via biorelevant dissolution and Raman imaging studies. Finally, an in vitro-in vivo correlation (IVIVC) model was developed using conventional and mechanistic deconvolution methods for comparison. The GastroPlus model accurately simulated oral Basmisanil exposure from tablets and granules formulations containing micronized drug. Absorption of oral doses below 200 mg was mostly dissolution rate-limited and thus particularly sensitive to formulation properties. Indeed, reduced exposure was observed for a 120-mg film-coated tablet and the slower dissolution rate measured in biorelevant media was attributed to differences in drug load. This hypothesis was confirmed when Raman imaging showed that the percolation threshold was exceeded in this formulation. This biorelevant dissolution method clearly differentiated between the formulations and was used to develop a robust IVIVC model. The study demonstrates the applicability and impact of mechanistic absorption modelling and biopharmaceutical in vitro tools for rational drug development.
authors.affiliation: Formulation Research & Development, F. Hoffmann-La Roche Ltd., Basel, Switzerland. cordula.stillhart@roche.com.
authors.forename: Cordula
authors.initials: C
authors.lastname: Stillhart
authors.affiliation: Pharmaceutical Research & Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Parrott
authors.affiliation: Analytical Development, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: Marc
authors.initials: M
authors.lastname: Lindenberg
authors.affiliation: Analytical Development, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Chalus
authors.affiliation: Clinical Pharmacology, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: Darren
authors.initials: D
authors.lastname: Bentley
authors.affiliation: Formulation Research & Development, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: Anikó
authors.initials: A
authors.lastname: Szepes
mesh_terms: D000284:Administration, Oral; D065546:Drug Liberation; D006801:Humans; D008962:Models, Theoretical; D010080:Oxazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012995:Solubility
chemical_list: D010080:Oxazoles; D011725:Pyridines
keywords: GastroPlus; absorption modelling; immediate-release formulation; in vitro-in vivo correlation; poorly water-soluble compound