title: Design of biorelevant test setups for the prediction of diclofenac in vivo features after oral administration.
abstract: OBJECTIVE
  Design of biorelevant test setups mimicking the physiological conditions experienced by drugs after oral administration along the passage through the mouth and the GI tract for the in vitro evaluation of diclofenac exhibiting multiple-peak phenomenon during absorption.
  
  
  METHODS
  The biorelevant models simulated successively saliva (SSF, pH 6.2-6.75-7.4, 5 mL, 3 min), gastric (SGF-FaSSGF, pH 1.2-1.6, 50-250 mL, 30 min) and intestinal (FaSSIF, pH 6.8, 250 mL, 60 min) fluids. Applying these models, diclofenac free acid and its sodium/potassium salt were comparatively evaluated for dissolution and further characterized by HPLC, optical morphogranulometry, DSC and PXRD to elucidate peculiar behaviors.
  
  
  RESULTS
  Diclofenac salts almost completely dissolved in SSF and showed a transitional dissolution pattern before complete precipitation in SGF/FaSSGF. This peculiar pattern correlated with simultaneous chemical modification and formation of agglomerates. With low dissolution in SSF and almost immediately complete precipitation, these behaviors were not observed with diclofenac free acid. Distinct diclofenac features were strongly determined by pH-modifications after oral administration.
  
  
  CONCLUSIONS
  The multiple-peak phenomenon observed after administrating a solution, suspension or dispersible formulation of diclofenac salts are likely caused by drug precipitation and agglomeration in the stomach leading to irregular gastric-emptying. Diclofenac free acid may provide more reliable in vivo features.
authors.affiliation: Institute of Pharmacy, Center of Drug Absorption and Transport, University of Greifswald, 17489 Greifswald, Germany.
authors.forename: Marie
authors.initials: M
authors.lastname: Guhmann
authors.forename: Markus
authors.initials: M
authors.lastname: Thommes
authors.forename: Frédéric
authors.initials: F
authors.lastname: Gerber
authors.forename: Norbert
authors.initials: N
authors.lastname: Pöllinger
authors.forename: Sandra
authors.initials: S
authors.lastname: Klein
authors.forename: Jörg
authors.initials: J
authors.lastname: Breitkreutz
authors.forename: Werner
authors.initials: W
authors.lastname: Weitschies
mesh_terms: D000284:Administration, Oral; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004008:Diclofenac / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism*; D005746:Gastric Emptying / Q000502:physiology; D005753:Gastric Mucosa / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption / Q000502:physiology*; D008954:Models, Biological; D010316:Particle Size; D019999:Pharmaceutical Solutions / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D012463:Saliva / Q000378:metabolism / Q000502:physiology; D012995:Solubility; D013270:Stomach / Q000502:physiology; D013535:Suspensions / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism
chemical_list: D019999:Pharmaceutical Solutions; D013535:Suspensions; D004008:Diclofenac
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