title: Investigation of solubilising effects of bile salts on an active pharmaceutical ingredient with unusual pH dependent solubility by NMR spectroscopy.
abstract: The interaction between an ampholytic and amphiphilic Active Pharmaceutical Ingredient (API) showing unusual pH dependent solubility and Fasted State Simulated Intestinal Fluid (FaSSIF) was studied by NMR spectroscopy. Solubility in FaSSIF was drastically increased, about 30 fold, compared to simulated gastrointestinal fluid without bile salts. Our studies aimed at understanding the mechanisms that lead to this drastic enhancement. All species present in solution at various concentrations of API were characterised by Diffusion Ordered Spectroscopy (DOSY) NMR measurements. These indicated the presence of mixed taurocholate-lecithin and pure taurocholate micelles in pure FaSSIF, and formation of mixed taurocholate-API micelles after addition of API. The formation of taurocholate-API micelles was also supported by Nuclear Overhauser Effect/Enhancement (NOE) contacts between taurocholate and the API. Formation of mixed taurocholate-API micelles took place at the expense of pure taurocholate micelles, whereas mixed taurocholate-lecithin micelles remained uninfluenced by the presence of API. Our results showed that the increase in solubility was due to similar amphiphilic properties of the API and taurocholate which enabled formation of mixed taurocholate-API micelles. From results of determination of solubility as well as NMR experiments a phase diagram comprising several micellar species was derived.
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Vogtherr
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Marx
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: A-C
authors.initials: AC
authors.lastname: Mieden
authors.affiliation: Merck KGaA, Darmstadt, Germany. Electronic address: christoph.saal@merckgroup.com.
authors.forename: C
authors.initials: C
authors.lastname: Saal
mesh_terms: D001647:Bile Acids and Salts / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D006863:Hydrogen-Ion Concentration; D007419:Intestinal Secretions / Q000378:metabolism*; D054709:Lecithins / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008823:Micelles; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000737:chemistry; D012995:Solubility; D013656:Taurocholic Acid / Q000737:chemistry*
chemical_list: D001647:Bile Acids and Salts; D054709:Lecithins; D008823:Micelles; D004364:Pharmaceutical Preparations; D013656:Taurocholic Acid
keywords: Biophysical models; Diffusion; Dissolution; Gastrointestinal; Micelles; NMR; Taurocholate–lecithin molecular species