PAMPA–Excipient Classification Gradient Map

Abstract

The effect of excipients on the artificial membrane permeability (Double-Sink PAMPA) properties of eight sparingly soluble drugs was studied. Quantities of excipient were selected to match the concentrations expected in the gastrointestinal fluid under clinically relevant conditions. Over 1,200 measurements were performed. To correct for the effects of the aqueous boundary layer and determine the intrinsic permeability, precisely measured ionization constants were used. The intrinsic permeability of weak acids was enhanced (up to 100 fold) but that of weak bases depressed (up to 270 fold) by the excipients: mefenamic acid > glybenclamide > progesterone > griseofulvin > clotrimazole > astemizole > dipyridamole > butacaine. Excipient enhancement ranked: 3 mM NaTC > 0.24% PEG400 > 0.2 M KCl > 0.24% NMP > 5% PEG400 > 0.24% PG > 1% PEG400 > 0.1M KCl > 1% PG > 1% NMP > 5% PG > 0.24% HP-beta-CD > 1% HP-beta-CD > 15 mM NaTC. The study clearly indicates that the method is suitable for use in preclinical development to assess the effect of excipients on the permeability of sparingly soluble drug candidates. The method is quick, cost-effective, and reasonably accurate. The self-rank-ordered PAMPA-Mapping may be a helpful visualization tool for delivery screening.

Solubility-Excipient Classification Gradient Maps

“…Quantities of the six excipients were selected to overlap the concentrations expected in the gastrointestinal fluid under clinically relevant conditions, as described previously (29). Briefly, KCl was selected at 0.1 and 0.2 M; sodium taurocholate (NaTC) solutions were prepared at 3 and 15 mM, corresponding to fasted and fed GIT states (35).…”

“…The high-precision pK a data, determined by the potentiometric method using the Gemini instrument (pION), were taken from Bendels et al (29). These were determined by extrapolation in methanolY Y Ywater solutions, taking advantage of the Gemini_s capability to determine pK a values even if there is precipitation during a portion of the titration, in either aqueous or cosolvent solutions.…”

“…In this study, we propose to extend to solubility-excipient measurement, the theme explored in a previous Double-Sink PAMPA excipient study (29), where we introduced the method of PAMPA-Mapping, based on eight sparingly soluble drugs (astemizole, butacaine, clotrimazole, dipyridamole, griseofulvin, progesterone, glibenclamide, and mefenemic acid), measured under 15 combinations of six excipients (sodium taurocholate, 2-hydroxypropyl-b-cyclodextrin, potassium chloride, propylene glycol, 1-methyl-2-pyrrolidone (33), and polyethylene glycol 400 (34)). Our aim was to develop a practical and cost-effective high-throughput (microtitre plate) assay, both compound-sparing and minimally compromising on accuracy, which could be used in early screening for solubility under GIT-relevant conditions of excipients.…”

Miniaturized Rotating Disk Intrinsic Dissolution Rate Measurement: Effects of Buffer Capacity in Comparisons to Traditional Wood’s Apparatus

“…In the case of furosemide, haloperidol, ketoprofen, and naproxen titrations, some precipitation was observed during the titration, but it was not necessary to resort to the traditional cosolvent method for these molecules, since the software in the Gemini Profiler allows for direct pK a determination when there is some precipitation during a portion of the titration (33,34). So, it appears to be possible to use aqueous media, provided the intrinsic solubility of the molecule, S o ≥2.5 µg/mL (that of haloperidol (19)).…”

Membrane Permeability – Measurement and Prediction in Drug Discovery

“…Such formulations are usually a combination of several excipients. Simultaneous assessment of solubility and permeability is required since formulation excipients may reduce the apparent permeability by reducing the free fraction of a drug [68].…”