title: Biopharmaceutic Profiling of Salts to Improve Absorption of Poorly Soluble Basic Drugs.
abstract: AZD1175 and AZD2207 are 2 highly lipophilic compounds with a significant risk of not achieving therapeutic plasma concentrations due to solubility-limited absorption. The compounds have the same molecular weight and minimal structural differences. The aim of the present work was to investigate whether salts could be applied to improve the intestinal absorption, and the subsequent in vivo exposure. Drug solubilities, dissolution rates, and degree of supersaturation and precipitation were determined in biorelevant media. Dog studies were performed, in the absence and presence of a precipitation inhibitor (hydroxypropyl methylcellulose). Finally, a human phase I study was performed. For AZD1175, there was a good agreement between dissolution rates, in vivo exposure in dog, and the obtained exposure in human with the selected hemi-1,5-naphthalenedisulfonate of the compound. For AZD2207, the picture was more complex. The same counter ion was selected for the study in man. In addition, the chloride salt of AZD2207 showed promising data in the presence of a precipitation inhibitor in vitro and in dog that, however, could not be repeated in man. The differences in observations between the 2 compounds could be attributed to the difference in solubility and to the degree of supersaturation in the gastric environment rather than in the intestine.
authors.affiliation: Department of Pharmacetical Technology and Development, AstraZeneca R&D Gothenburg, Mölndal S-431 83, Sweden.
authors.forename: Christer
authors.initials: C
authors.lastname: Tannergren
authors.affiliation: Department of Pharmacetical Technology and Development, AstraZeneca R&D Gothenburg, Mölndal S-431 83, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Karlsson
authors.affiliation: Department of Pharmaceutical Sciences, AstraZeneca R&D Gothenburg, Mölndal S-431 83, Sweden.
authors.forename: Kalle
authors.initials: K
authors.lastname: Sigfridsson
authors.affiliation: Department of Pharmaceutical Sciences, AstraZeneca R&D Gothenburg, Mölndal S-431 83, Sweden.
authors.forename: Lennart
authors.initials: L
authors.lastname: Lindfors
authors.affiliation: Department of Pharmaceutical Sciences, AstraZeneca R&D Gothenburg, Mölndal S-431 83, Sweden.
authors.forename: Angela
authors.initials: A
authors.lastname: Ku
authors.affiliation: Department of Pharmaceutical Sciences, AstraZeneca R&D Gothenburg, Mölndal S-431 83, Sweden.
authors.forename: Britta
authors.initials: B
authors.lastname: Polentarutti
authors.affiliation: Department of Pharmaceutical Sciences, AstraZeneca R&D Gothenburg, Mölndal S-431 83, Sweden. Electronic address: sara.carlert@astrazeneca.com.
authors.forename: Sara
authors.initials: S
authors.lastname: Carlert
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001702:Biopharmaceutics / Q000379:methods*; D063387:Cannabinoid Receptor Antagonists / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism*; D018592:Cross-Over Studies; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology; D008297:Male; D012492:Salts / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism*; D012995:Solubility
chemical_list: D063387:Cannabinoid Receptor Antagonists; D012492:Salts
keywords: bioavailability; dissolution; intestinal absorption; pharmacokinetics; precipitation; salts; solubility-limited absorption; supersaturation