Clinically relevant in vitro dissolution/release testing for parenteral formulations

  • Ricardo Diaz De Leon Ortega

Student thesis: Doctoral ThesisPhD


The information available on in vitro release testing for controlled release parenteral formulations is limited. Thus investigating the effect of different media components and hydrodynamic setups in order to develop an in vitro release test that could predict the in vivo performance of parenteral formulations is needed.
The aim of this thesis was to develop an in vitro release test that coupled with in silico modeling could predict the in vivo release of a parenteral drug formulation administered intravenously [using Amphotericin B liposomal formulation (Ambisome®) as formulation model)]. Amphotericin B is a poorly soluble and highly protein bound drug, therefore the effect of albumin on Amphotericin B solubility, degradation and microbiological activity was investigated. Biorelevant and clinically relevant media were developed and used with two hydrodynamics setups for the in vitro release testing of Ambisome®. Compartmental pharmacokinetic (PK) and physiologically-based pharmacokinetic (PBPK) modeling were performed in data from healthy subjects receiving Ambisome® in order to relate the in vitro release profiles to the in vivo release profile. The PBPK model was extrapolated to a hypoalbuminaemic population and used to evaluate the antifungal effect of Amphotericin B on Candida albicans. Albumin was of high importance in the test media as it increases the solubility and degradation rate of Amphotericin B, while it decreases its microbiological activity. In vitro release tests in biorelevant media with the sample and separate setup was successful to predict in vivo AmB release, assessed with the use of PK modeling. Prediction of the AmB liposomal and released plasma concentrations was achieved with the development of a PBPK model in which the in vitro release profiles in the developed media (clinically relevant media with biorelevant surfactants) were used. In the simulated hypoalbuminaemic population, the PBPK/PD model developed revealed that the microbiological activity of Amphotericin B was increased due to a decrease in albumin concentration (leading to more drug available to exert a pharmacological effect).
This thesis provides an overview of how relevant media components and hydrodynamics affect the release of drug from an intravenously administered parenteral formulation and linked with either PK or PBPK modeling could predict the in vivo behaviour of the formulation and the released drug. This could be a starting point for the future development of clinically relevant in vitro release testing for more parenteral formulations.
Date of Award3 Apr 2019
Original languageEnglish
Awarding Institution
  • University of Bath
SupervisorCharareh Pourzand (Supervisor) & Nikoletta Fotaki (Supervisor)

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