title: Solubility-excipient classification gradient maps.
abstract: This study assessed the effect of excipients (sodium taurocholate, 2-hydroxypropyl-f-cyclodextrin, potassium chloride, propylene glycol, 1-methyl-2-pyrrolidone, and polyethylene glycol 400) on the apparent intrinsic solubility properties of eight sparingly soluble drugs (four bases, two neutrals, and two acids): astemizole, butacaine, clotrimazole, dipyridamole, griseofulvin, progesterone, glibenclamide, and mefenemic acid. Over 1,200 UV-based solubility measurements (pH 3-10) were made with a high-throughput instrument. New equations, based on the "shift-in-pKa" method, were derived to interpret the complicated solubility-pH dependence observed, and poorly predicted by the Henderson-Hasselbalch equation. An intrinsic solubility-excipient classification gradient map visualization tool was developed to rank order the compounds and the excipients. In excipient-free solutions, all of the ionizable compounds formed either uncharged or mixed-charge aggregates. Mefenamic acid formed anionic dimers and trimers. Glibenclamide displayed a tendency to form monoanionic dimers. Dipyridamole and butacaine tended to form uncharged aggregates. With strong excipients, the tendency to form aggregates diminished, except in the case of glibenclamide. We conclude that a low-cost, compound-sparing, and reasonably accurate high-throughput assay which can be used in early screening to prioritize candidate molecules by their eventual developability via the excipient route is possible with the aid of the "self-organized" intrinsic solubility-excipient classification gradient maps.
authors.affiliation: pION INC, 5 Constitution Way Woburn, MA 01801, USA. aavdeef@pion-inc.com
authors.forename: Alex
authors.initials: A
authors.lastname: Avdeef
authors.forename: Stefanie
authors.initials: S
authors.lastname: Bendels
authors.forename: Oksana
authors.initials: O
authors.lastname: Tsinman
authors.forename: Konstantin
authors.initials: K
authors.lastname: Tsinman
authors.forename: Manfred
authors.initials: M
authors.lastname: Kansy
mesh_terms: D000465:Algorithms; D005079:Excipients / Q000737:chemistry* / Q000145:classification*; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D012995:Solubility
chemical_list: D005079:Excipients; D004364:Pharmaceutical Preparations