An Artificial Gut/Absorption Simulator: Simultaneous Evaluation of Desupersaturation and Absorption from Ketoconazole Supersaturated Solutions

Krutika Meena Harish Jain, Hao Helen Hou, Ronald A. Siegel

Research output: Contribution to journalArticlepeer-review

Abstract

For supersaturating formulations of BCS-II compounds, which by definition have high intestinal permeability, a closed USP apparatus does not provide the necessary absorptive conditions during dissolution. To address this, an artificial gut simulator (AGS) has been constructed consisting of a 2.5 mL donor compartment in which a hollow fiber-based absorption module is suspended. Drug from donor diffuses across the hollow fiber membrane to be absorbed by the continuously flowing intraluminal receiver fluid. The membrane surface area and intraluminal fluid flow rate are tuned to obtain the physiologically observed absorption rate constant for a weakly basic, poorly water-soluble model compound, ketoconazole (KTZ). Supersaturated solutions of KTZ were generated in the donor in pH 6.5 phosphate buffer by the pH-shift method in the absence (closed system, control) and presence (open system, biorelevant) of an optimally or suboptimally tuned absorption module. Drug concentrations in the donor and intraluminal fluids were determined by in-line UV spectroscopy. The presence of an absorptive sink reduced the supersaturated solution's crystallization propensity, more so in the case of the optimally tuned AGS. This study demonstrates the significance of simulating absorption of drug at a physiological rate during dissolution studies, especially to predict the performance of formulations of BCS-II drugs.

Original languageEnglish (US)
JournalJournal of Pharmaceutical Sciences
DOIs
StateAccepted/In press - 2022

Bibliographical note

Funding Information:
The authors acknowledge Genentech Inc. for providing research funding and scientific input as well as a Bighley Graduate Fellowship (2017-2018, 2018-2019) and Rowell Fellowship (2018-2019) for financial support for Krutika Meena Harish Jain. University of Minnesota, Twin Cities and Genentech Inc. jointly participated in study design, research, data interpretation, discussion, writing, reviewing and approving the publication. Data sets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Funding Information:
The authors acknowledge Genentech Inc., for providing research funding and scientific input as well as a Bighley Graduate Fellowship (2017-2018, 2018-2019) and Rowell Fellowship (2018-2019) for financial support for Krutika Meena Harish Jain. University of Minnesota, Twin Cities and Genentech Inc. jointly participated in study design, research, data interpretation, discussion, writing, reviewing and approving the publication.

Publisher Copyright:
© 2022

Keywords

  • Absorption
  • Amorphous
  • Crystallization
  • In vitro model
  • Membrane transport
  • Passive diffusion
  • Phase separation
  • Precipitation
  • Supersaturation

PubMed: MeSH publication types

  • Journal Article

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