title: 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.
abstract: OBJECTIVE
  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.
authors: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, 3052, Australia.
authors: Hywel D
authors: HD
authors: Williams
authors: Philip
authors: P
authors: Sassene
authors: Karen
authors: K
authors: Kleberg
authors: Marilyn
authors: M
authors: Calderone
authors: Annabel
authors: A
authors: Igonin
authors: Eduardo
authors: E
authors: Jule
authors: Jan
authors: J
authors: Vertommen
authors: Ross
authors: R
authors: Blundell
authors: Hassan
authors: H
authors: Benameur
authors: Anette
authors: A
authors: Müllertz
authors: Colin W
authors: CW
authors: Pouton
authors: Christopher J H
authors: CJ
authors: Porter
mesh_terms: D011232:Chemical Precipitation; D003460:Crystallization; D004063:Digestion; D011345:Fenofibrate / Q000008:administration & dosage* / Q000737:chemistry; D006801:Humans; D000960:Hypolipidemic Agents / Q000008:administration & dosage* / Q000737:chemistry; D007422:Intestines / Q000502:physiology; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry*; D014677:Pharmaceutical Vehicles / Q000737:chemistry*; D012995:Solubility; D062367:ortho-Aminobenzoates / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D000960:Hypolipidemic Agents; D008055:Lipids; D014677:Pharmaceutical Vehicles; D062367:ortho-Aminobenzoates; C009500:tolfenamic acid; D011345:Fenofibrate
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