Investigation and simulation of dissolution with concurrent degradation under healthy and hypoalbuminaemic simulated parenteral conditions- case example Amphotericin B

Ricardo Diaz De Leon-Ortega, Deirdre Maria D'Arcy, A. Bolhuis, N. Fotaki

Research output: Contribution to journalArticlepeer-review

6 Citations (SciVal)
124 Downloads (Pure)

Abstract

Guidance on dissolution testing for parenteral formulations is limited and not often related in vivo performance. Critically ill patients represent a target cohort, frequently hypoalbuminaemic, to whom certain parenteral formulations are administered. Amphotericin B (AmB) is a poorly soluble, highly protein-bound drug, available as lipid-based formulations and used in critical illness. The aim of this study was to develop media representing hypoalbuminaemic and healthy plasma, and to understand and simulate the dissolution profile of AmB in biorelevant media. Dissolution media were prepared with bovine serum albumin (BSA) in Krebs-Ringer buffer, and tested in a flow through cell apparatus and a bottle/stirrer setup. Drug activity was tested against Candida albicans. BSA concentration was positively associated with solubility, degradation rate and maximum amount dissolved and negatively associated with dissolution rate constant and antifungal activity. In the bottle/stirrer setup, a biexponential model successfully described simultaneous dissolution and degradation and increased in agitation reduced the discriminatory ability of the test. The hydrodynamics provided by the flow-through cell apparatus was not adequate to dissolve the drug. Establishing discriminating test methods with albumin present in the dissolution media, representing the target population, supports future development of biorelevant and clinically relevant tests for parenteral formulations.

Original languageEnglish
Pages (from-to)423-431
Number of pages9
JournalEuropean Journal of Pharmaceutics and Biopharmaceutics
Volume127
Early online date27 Mar 2018
DOIs
Publication statusPublished - 1 Jun 2018

Keywords

  • Albumin
  • Amphotericin B
  • Biorelevant
  • Degradation
  • Dissolution
  • Hypoalbuminaemia
  • Solubility

ASJC Scopus subject areas

  • Biotechnology
  • Pharmaceutical Science

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