title: Biorelevant solubility of poorly soluble drugs: rivaroxaban, furosemide, papaverine and niflumic acid.
abstract: In this work the biorelevant solubility of four drugs representing different acid-base property, wide range of lipohilicity and low aqueous solubility was studied. The equilibrium solubility of rivaroxaban (non-ionizable), furosemide (acid), papaverine (base) and niflumic acid (ampholyte) was determined in simulated gastric fluid (SGF pH 1.2), in simulated intestinal fluid fasted state (FaSSIF pH 6.5) and fed state (FeSSIF pH 5.0) and their corresponding blank buffers at a temperature of 37 °C using saturation shake-flask method. The concentration was measured by optimized HPLC analysis. The solubilizing effect of bile acid/lipid micelles as additive components of biorelevent media (BRM) is expressed with the solubility ratio (SR: SBRM/Sblank buffer) and the food effect was estimated from SFeSSIF/SFaSSIF coefficient. It was revealed that ionization plays primarily role in solubility of compounds which undergo ionization in BRM. The solubilizing effect in FaSSIF was marginal for the neutral compound (rivaroxaban) and for molecules are anionic at pH 6.5 (furosemide and niflumic acid). The higher concentration of solubilizing agents in FeSSIF improved the solubility of papaverine carrying positive charge and niflumic acid being partially zwitterionic at pH 5.0.
authors.affiliation: Department of Pharmaceutical Chemistry, Semmelweis University, H-1092 Hőgyes Endre street 9, Budapest, Hungary. novak.krisztina@pharma.semmelweis-univ.hu
authors.forename: Krisztina
authors.initials: K
authors.lastname: Takács-Novák
authors.forename: Vera
authors.initials: V
authors.lastname: Szőke
authors.forename: Gergely
authors.initials: G
authors.lastname: Völgyi
authors.forename: Péter
authors.initials: P
authors.lastname: Horváth
authors.forename: Rita
authors.initials: R
authors.lastname: Ambrus
authors.forename: Piroska
authors.initials: P
authors.lastname: Szabó-Révész
mesh_terms: D001647:Bile Acids and Salts / Q000737:chemistry; D001826:Body Fluids / Q000737:chemistry; D005665:Furosemide / Q000737:chemistry*; D005766:Gastrointestinal Contents / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D007422:Intestines / Q000737:chemistry; D008055:Lipids / Q000737:chemistry; D008823:Micelles; D009025:Morpholines / Q000737:chemistry*; D009544:Niflumic Acid / Q000737:chemistry*; D010208:Papaverine / Q000737:chemistry*; D000069552:Rivaroxaban; D012995:Solubility; D013876:Thiophenes / Q000737:chemistry*
chemical_list: D001647:Bile Acids and Salts; D008055:Lipids; D008823:Micelles; D009025:Morpholines; D013876:Thiophenes; D009544:Niflumic Acid; D005665:Furosemide; D000069552:Rivaroxaban; D010208:Papaverine