Selection and analysis of predictive fed-state gastric biorelevant media

Abstract

Dissolution testing is a tool towards prediction of dosage form behaviour under physiologically relevant conditions. The use of simple aqueous media dictated by the pharmacopoeias cannot predict the drug’s in vivo response as their physicochemical properties differ significantly from the complex environment of the gastrointestinal tract. To improve the predictive potential of drug dissolution, the development of more “biorelevant” media is essential. In particular, simulating drug dissolution in the gastric environment after administration of a meal still remains a challenge. Furthermore, except for the optimisation of the medium composition, the analysis of these usually complex heterogeneous media has also been challenging, due to the lack of a unified guideline for the selection of medium and analytical assay. The principal aim of the thesis was the development of a simple and robust analytical methodology, optimised on the basis of the drug’s physicochemical properties, interaction with excipients in a formulation and fat partitioning behaviour. The potential use of sample clean-up techniques including protein precipitation (PP) and solid phase extraction (SPE) was investigated. Optimised clean-up protocols were successfully used for extraction and quantification of drugs of a wide range of lipophilicity in milk-based fed biorelevant media.It was demonstrated that prior knowledge of the active ingredient’s physicochemical properties, such as log P, aqueous solubility, ionisation and protein binding can be used towards the selection of optimum extraction conditions. Moreover, the presence of certain excipients, when mixed with the APIs can significantly affect the methods’ efficiency and must thereforebe taken into consideration during analytical method development. Interactions between active ingredients and lipid part of the fed gastric content were also investigated, via development of biphasic “drug partition to fat” in vitro setups. The rate of drug partition to fat was successfully predicted based on the drug’s physicochemical properties and in vivo food effect. Finally, a simpler medium, alternative to Fed State Simulated Gastric Fluid (FeSSGF) was developed, requiring a less laborious extraction protocol. Overall, this thesis has provided useful insight on the critical aspects of fed gastric medium and analytical methodology development. It provides a point of reference for future work on better understanding on drug solubilisation in the gastric fed state and correlation with in vivo food effect.

Date of Award	15 Nov 2017
Original language	English
Awarding Institution	University of Bath
Sponsors	Merck Sharp & Dohme Limited
Supervisor	Nikoletta Fotaki (Supervisor)