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.

Suggested Improvements for Measurement of Equilibrium Solubility-pH of Ionizable Drugs

“…If the pK a is known, then it is not necessary to assume that the HH equation holds, as has been demonstrated by Avdeef et al [74].…”

Molecular Buckets: Cyclodextrins for Oral Cancer Therapy

“…Worldwide, more than 30 different drugs are currently marketed as solid or solution-based CD complex formulations (Table 2) [35,39]. In these pharmaceutical products, CDs are mainly used as complexing agents to increase the aqueous solubility of poorly water-soluble drugs and, thus, their bioavailability and stability [40][41][42].…”

Drug Ionization and Physicochemical Profiling

“…The resultant aqueous solutions are often complicated by the presence of not only multiply charged forms of drug, but also by the presence of aggregates, micelles and complexes (formed with constituents of the dissolution medium) [20, 72 -75] . The interpretation of solubility -pH curves can be challenging, and the inference of pH dependence from single pH measurements based on the use of the Henderson -Hasselbalch equation can be unreliable [15,20] . If not long enough a time is taken for the solubility equilibration, measured results are complicated by time -dependent changes.…”

“…The equations for other more complicated cases are summarized elsewhere [76] . Figure 3.2(a) shows a plot of log S versus pH for naproxen, based on re -analysis (unpublished) of the shake -fl ask [49,77] and microtiter plate [20] data reported in the literature. The dashed curves in Fig.…”

“…Section 3.4 considers solubility pH profi les, which can indicate the true p K a , and, under certain conditions, the " Gibbs ' p K a " [19] . Furthermore, from the shape of the hyperbolicsigmoidal curves and the value of the " apparent p K a , " it is possible to recognize the presence and the charge state of aggregates of low -soluble molecules [20] . Section 3.5 deals with permeability profi les, based on cellular models (Caco -2, MDCK, etc.)…”