Merck

Ionic liquid versus prodrug strategy to address formulation challenges.

Pharmaceutical research (2014-12-24)
Anja Balk, Toni Widmer, Johannes Wiest, Heike Bruhn, Jens-Christoph Rybak, Philipp Matthes, Klaus Müller-Buschbaum, Anastasios Sakalis, Tessa Lühmann, Jörg Berghausen, Ulrike Holzgrabe, Bruno Galli, Lorenz Meinel
ABSTRACT

A poorly water soluble acidic active pharmaceutical ingredient (API) was transformed into an ionic liquid (IL) aiming at faster and higher oral availability in comparison to a prodrug. API preparations were characterized in solid state by single crystal and powder diffraction, NMR, DSC, IR and in solution by NMR and ESI-MS. Dissolution and precipitation kinetics were detailed as was the role of the counterion on API supersaturation. Transepithelial API transport through Caco-2 monolayers and counterion cytotoxicity were assessed. The mechanism leading to a 700 fold faster dissolution rate and longer duration of API supersaturation of the ionic liquid in comparison to the free acid was deciphered. Transepithelial transport was about three times higher for the IL in comparison to the prodrug when substances were applied as suspensions with the higher solubility of the IL outpacing the higher permeability of the prodrug. The counterion was nontoxic with IC50 values in the upper μM / lower mM range in cell lines of hepatic and renal origin as well as in macrophages. The IL approach was instrumental for tuning physico-chemical API properties, while avoiding the inherent need for structural changes as required for prodrugs.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Phenol Red, powder, BioReagent, suitable for cell culture
Sigma-Aldrich
DAPI, for nucleic acid staining
Sigma-Aldrich
Sodium phosphate, 96%
Sigma-Aldrich
Acetonitrile, anhydrous, 99.8%
Sigma-Aldrich
Potassium, chunks (in mineral oil), 98% trace metals basis
Sigma-Aldrich
Sodium bicarbonate-12C, 99.9 atom % 12C
Sigma-Aldrich
Potassium hydride, 30 wt % dispersion in mineral oil
Sigma-Aldrich
Phenol Red, ACS reagent
Sigma-Aldrich
Fluorescein, for fluorescence, free acid
Sigma-Aldrich
5α-Androstan-17β-ol-3-one, purum, ≥99.0% (TLC)
Sigma-Aldrich
Potassium hydride, in paraffin
Sigma-Aldrich
Sodium hydroxide-16O solution, 20 wt. % in H216O, 99.9 atom % 16O
Sigma-Aldrich
Acetonitrile, Preparateur, ≥99.9% (GC), One-time steel-plastic (SP) drum
Sigma-Aldrich
Potassium, cubes (in mineral oil), 99.5% trace metals basis
Sigma-Aldrich
Acetonitrile, for DNA synthesis
Sigma-Aldrich
Acetonitrile, Preparateur, ≥99.9% (GC), Customized plastic drum
Sigma-Aldrich
Potassium hydroxide on alumina
Sigma-Aldrich
Ultrapure Acetonitrile
Sigma-Aldrich
Potassium hydroxide, anhydrous, ≥99.95% trace metals basis
Sigma-Aldrich
Acetonitrile, electronic grade, 99.999% trace metals basis
Sigma-Aldrich
Sodium bicarbonate, Hybri-Max, powder, suitable for hybridoma, ≥99.5%
Sigma-Aldrich
Streptomycin sulfate salt, powder, BioReagent, suitable for cell culture
Sigma-Aldrich
Potassium chloride, powder, BioReagent, suitable for cell culture, suitable for insect cell culture, ≥99.0%
Sigma-Aldrich
Potassium chloride solution, 0.075 M, sterile-filtered, BioXtra, suitable for cell culture
Sigma-Aldrich
Potassium chloride, for molecular biology, ≥99.0%
Sigma-Aldrich
Streptomycin sulfate salt, suitable for plant cell culture
Supelco
Hydrochloric acid solution, volumetric, 0.1 M HCl (0.1N), endotoxin free
Sigma-Aldrich
Potassium chloride, BioXtra, ≥99.0%
Sigma-Aldrich
Hydrochloric acid solution, 1.0 N, BioReagent, suitable for cell culture
Sigma-Aldrich
Streptomycin sulfate salt, powder, BioXtra, suitable for mouse embryo cell culture