Toward the establishment of standardized in vitro tests for lipid-based formulations, part 3: understanding supersaturation versus precipitation potential during the in vitro digestion of type I, II, IIIA, IIIB and IV lipid-based formulations

Research output: Contribution to journalJournal articleResearchpeer-review

  • Hywel D Williams
  • Philip Sassene
  • Karen Kleberg
  • Marilyn Calderone
  • Annabel Igonin
  • Eduardo Jule
  • Jan Vertommen
  • Ross Blundell
  • Hassan Benameur
  • Müllertz, Anette
  • Colin W Pouton
  • Christopher J H Porter
  • LFCS Consortium

PURPOSE: Recent studies have shown that digestion of lipid-based formulations (LBFs) can stimulate both supersaturation and precipitation. The current study has evaluated the drug, formulation and dose-dependence of the supersaturation - precipitation balance for a range of LBFs.

METHODS: Type I, II, IIIA/B LBFs containing medium-chain (MC) or long-chain (LC) lipids, and lipid-free Type IV LBF incorporating different doses of fenofibrate or tolfenamic acid were digested in vitro in a simulated intestinal medium. The degree of supersaturation was assessed through comparison of drug concentrations in aqueous digestion phases (APDIGEST) during LBF digestion and the equilibrium drug solubility in the same phases.

RESULTS: Increasing fenofibrate or tolfenamic acid drug loads (i.e., dose) had negligible effects on LC LBF performance during digestion, but promoted drug crystallization (confirmed by XRPD) from MC and Type IV LBF. Drug crystallization was only evident in instances when the calculated maximum supersaturation ratio (SR(M)) was >3. This threshold SR(M) value was remarkably consistent across all LBF and was also consistent with previous studies with danazol.

CONCLUSIONS: The maximum supersaturation ratio (SR(M)) provides an indication of the supersaturation 'pressure' exerted by formulation digestion and is strongly predictive of the likelihood of drug precipitation in vitro. This may also prove effective in discriminating the in vivo performance of LBFs.

Original languageEnglish
JournalPharmaceutical Research
Issue number12
Pages (from-to)3059-76
Number of pages18
Publication statusPublished - Dec 2013

    Research areas

  • Chemical Precipitation, Crystallization, Digestion, Fenofibrate, Humans, Hypolipidemic Agents, Intestines, Lipid Metabolism, Lipids, Pharmaceutical Vehicles, Solubility, ortho-Aminobenzoates

ID: 120402611