title: Early pharmaceutical evaluation of a crystalline and hygroscopic GABAB receptor agonist.
abstract: Lesogaberan is a potent gamma amino butyric acid agonist and has been evaluated for its utility in treatment of gastroesophageal reflux disease. Lesogaberan is a crystalline substance that absorbs considerable amounts of water above 65% relative humidity (RH) where it also liquifies. As a result of the hygroscopicity of the zwitterionic form an investigation of different salt forms was performed. Since the test compound is polar and lacks ultraviolet (UV) chromophore, conventional separation and detection techniques could not be used to characterise the test compound and the impurities. The analytical techniques are described, focusing on the capillary electrophoresis method with indirect UV detection for purity, the liquid chromatographic method for enantiomeric separation with derivatisation with UV chromophore and two complementary nuclear magnetic resonance (NMR) approaches (¹⁹F-NMR and ¹H-NMR) for impurities. The stability study in solution showed that solutions between pH 5 and 7 were the most stable ones, but after some time degradation occurred at room temperature. When bulk lesogaberan was stored at 25°C/60% RH no chemical degradation was observed after 1 year. At 40°C/75% RH, where the compound liquefies, a significant degradation was observed after 1 month. However, in a closed container (= 40°C) or as a napsylate salt, no degradation of lesogaberan was observed at 40°C/75% RH.
authors.affiliation: Pharmaceutical Development, Astrazeneca R&D Mölndal, S-431 83 Mölndal, Sweden. carl-gustav.sigfridsson@astrazeneca.com
authors.forename: Kalle
authors.initials: K
authors.lastname: Sigfridsson
authors.forename: Thomas
authors.initials: T
authors.lastname: Andersson
authors.forename: Veronica
authors.initials: V
authors.lastname: Berntsson
authors.forename: Yudong
authors.initials: Y
authors.lastname: Wang
mesh_terms: D002851:Chromatography, High Pressure Liquid; D004340:Drug Contamination; D004355:Drug Stability; D004356:Drug Storage; D019075:Electrophoresis, Capillary; D058785:GABA-A Receptor Agonists / Q000032:analysis / Q000737:chemistry*; D005765:Gastrointestinal Agents / Q000032:analysis / Q000737:chemistry*; D006358:Hot Temperature / Q000009:adverse effects; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008855:Microscopy, Electron, Scanning; D010316:Particle Size; D010721:Phosphinic Acids / Q000032:analysis / Q000737:chemistry*; D033362:Powder Diffraction; D011437:Propylamines / Q000032:analysis / Q000737:chemistry*; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism
chemical_list: D058785:GABA-A Receptor Agonists; D005765:Gastrointestinal Agents; D010721:Phosphinic Acids; D011437:Propylamines; C545087:lesogaberan