Absorption-excipient-pH classification gradient maps: Sparingly soluble drugs and the pH partition hypothesis

This study of sparingly soluble model drugs assesses (a) how pH and the aqueous boundary layer factors may affect in vitro and in vivo absorption, (b) to what extent single excipients (sodium taurocholate, hydroxypropyl-β-cyclodextrin, KCl, propylene glycol, methylpyrrolidone, and polyethylene glycol 400) can mitigate adverse absorption effects, and (c) how a novel rank-order visualization tool can be applied in high-throughput screening to identify promising single-excipient effects on the absorption potential of test compounds. The products of accurately measured solubility and artificial-membrane permeability (PAMPA) values at pH 5.0, 6.2, and 7.4, fully taking into account factors such as aqueous boundary layer resistance, membrane retention, and the formation of drug dimers and trimers, were used to define a flux function. A “self-organized” data visualization tool based on the flux function was mined for the promising excipient-drug combinations. In excipient-free solutions, most of the compounds studied formed aggregates. The presence of an excipient predominantly lowered permeability, but most often not by the same amount as solubility was elevated. The compounds with absorption potential most helped by excipients were: clotrimazole > griseofulvin > progesterone > dipyridamole > glibenclamide > mefenamic acid > butacaine > astemizole. The HP-β-CD effect observed for albendazole and glibenclamide appeared to follow Cmax trends in published pharmacokinetics studies. A surprising outcome of the in vitro measurements was that the classical pH Partition Hypothesis can be “inverted” in its monotonicity by sparingly soluble compounds.