Solubility-Excipient Classification Gradient Maps

• Published in: Pharmaceutical research Vol. 24; no. 3; pp. 530 - 545
• Main Authors: Avdeef, Alex, Bendels, Stefanie, Tsinman, Oksana, Tsinman, Konstantin, Kansy, Manfred
• Format: Journal Article
• Language: English
• Published: New York, NY Springer 01.03.2007; Springer Nature B.V
• Subjects: Algorithms; Biological and medical sciences; Excipients - chemistry; Excipients - classification; General pharmacology; Hydrogen-Ion Concentration; Kinetics; Mathematics; Measurement techniques; Medical sciences; Molecular Structure; Pharmaceutical industry; Pharmaceutical Preparations - chemistry; Pharmaceutical technology. Pharmaceutical industry; Pharmacology; Pharmacology. Drug treatments; R&D; Research & development; Solubility; sodium taurocholate; Pharmaceutical technology; propylene glycol; Vehicle(excipient); Solubility; Double-Sink PAMPA; HP-p-CD; PEG400; Classification; low solubility; intrinsic solubility-excipient mapping; methylpyrrolidone; Propanediol; excipients; Physicochemical properties
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-006-9169-0

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.