title: The impact of reduced gastric acid secretion on dissolution of salts of weak bases in the fasted upper gastrointestinal lumen: Data in biorelevant media and in human aspirates.
abstract: OBJECTIVE
  To propose media for simulating the intragastric environment under reduced gastric acid secretion in the fasted state at three levels of simulation of the gastric environment and evaluate their usefulness in evaluating the intragastric dissolution of salts of weak bases. To evaluate the importance of bicarbonate buffer in biorelevant in vitro dissolution testing when using Level II biorelevant media simulating the environment in the fasted upper small intestine, regardless of gastric acid secretions.
  
  
  METHODS
  Media for simulating the hypochlorhydric and achlorhydric conditions in stomach were proposed using phosphates, maleates and bicarbonates buffers. The impact of bicarbonates in Level II biorelevant media simulating the environment in upper small intestine was evaluated so that pH and bulk buffer capacity were maintained. Dissolution data were collected using two model compounds, pioglitazone hydrochloride and semifumarate cocrystal of Compound B, and the mini-paddle dissolution apparatus in biorelevant media and in human aspirates.
  
  
  RESULTS
  Simulated gastric fluids proposed in this study were in line with pH, buffer capacity, pepsin content, total bile salt/lecithin content and osmolality of the fasted stomach under partial and under complete inhibition of gastric acid secretion. Fluids simulating the conditions under partial inhibition of acid secretion were useful in simulating concentrations of both model compounds in gastric aspirates. Bicarbonates in Level III biorelevant gastric media and in Level II biorelevant media simulating the composition in the upper intestinal lumen did not improve simulation of concentrations in human aspirates.
  
  
  CONCLUSIONS
  Level III biorelevant media for simulating the intragastric environment under hypochlorhydric conditions were proposed and their usefulness in the evaluation of concentrations of two model salts of weak bases in gastric aspirates was shown. Level II biorelevant media for simulating the environment in upper intestinal lumen led to underestimation of concentrations in aspirates, even when bicarbonate buffer was used.
authors.affiliation: Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Zografou, Greece.
authors.forename: Chara
authors.initials: C
authors.lastname: Litou
authors.affiliation: Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Zografou, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Vertzoni
authors.affiliation: Pharmaceutical Sciences and Clinical Supply, Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Pharmaceutical Sciences and Clinical Supply, Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Filippos
authors.initials: F
authors.lastname: Kesisoglou
authors.affiliation: Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Zografou, Greece. Electronic address: reppas@pharm.uoa.gr.
authors.forename: Christos
authors.initials: C
authors.lastname: Reppas
mesh_terms: D001639:Bicarbonates / Q000378:metabolism; D002021:Buffers; D004063:Digestion / Q000502:physiology; D005215:Fasting / Q000378:metabolism*; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000378:metabolism*; D005766:Gastrointestinal Contents / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007421:Intestine, Small / Q000378:metabolism; D009994:Osmolar Concentration; D012492:Salts / Q000378:metabolism*; D012995:Solubility
chemical_list: D001639:Bicarbonates; D002021:Buffers; D012492:Salts
keywords: Achlorhydria; Biorelevant media; Dissolution; Human aspirates; Hypochlorhydria; Pioglitazone hydrochloride; Weak bases