Understanding interactions of oleic acid with basic drugs in solid lipids on different biopharmaceutical levels

  • Zdravka Misic University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences, Institute of Pharma Technology, Gründenstr. 40, 4132 Muttenz, Switzerland University of Basel, Department of Pharmaceutical Sciences, Klingelbergerstr. 50, 4056 Basel, Switzerland
  • Dubravka Šišak Jung Laboratory for Crystallography, ETH Zürich, Wolfgang-Pauli-Str. 10, 8093 Zürich, Switzerland
  • Georg Sydow Swiss Caps AG, member of the Aenova group, Husenstr. 35, 9533 Kirchberg, Switzerland
  • Martin Kuentz University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences, Institute of Pharma Technology, Gründenstr. 40, 4132 Muttenz, Switzerland

Abstract

Recently, the impact of intestinal supersaturation on absorption of poorly water-soluble drugs has raised much interest among researchers. A focus has been mostly to study excipient effects on maintenance of drug supersaturation. The aim of the present study was to better understand the effects of drug-excipient interactions on the level of the anhydrous formulation, upon dispersion in simple buffer media and, in particular, regarding precipitation kinetics. A solid lipid-based formulation comprising PEG-32 stearate and oleic acid (OA) (8:2 w/w) was developed as a model. Loratadine (pKa = 4.33) and carvedilol (pKa = 8.74) were chosen as basic drugs. UV/FTIR spectroscopy and viscometry were used to characterize drug-OA molecular interactions in solution, while solid formulations were studied using x-ray diffraction, thermal analysis and van’t Hoff solubility-temperature plots. Precipitation kinetics of drug formulations was real-time monitored in phosphate buffer (pH = 6.5) by focused beam reflectance measurements. It was found that the addition of OA in the formulations resulted in substantial drug solubility increase. Although the drug-OA interactions appeared to be partially lost upon formulation dispersion, the extent of precipitation was markedly lowered compared to the formulations without OA. A Precipitation number (Pnc) was introduced as a ratio of a relevant residence time of drug in the gastrointestinal tract (GIT) to the induction time (the onset time of crystalline precipitation). Without OA, Pnc was already taking critical values (>1), while the anhydrous formulation was still below saturation for both model drugs. Interestingly, the addition of OA resulted in amorphous instead of crystalline precipitates, which is advantageous for drug re-dissolution and absorption. In conclusion, this study provides an improved understanding of OA and basic drug interactions on different levels of in vitro performance for more rational oral formulation development.

Published
2014-06-25
How to Cite
MISIC, Zdravka et al. Understanding interactions of oleic acid with basic drugs in solid lipids on different biopharmaceutical levels. Journal of Excipients and Food Chemicals, [S.l.], v. 5, n. 2, p. 113-134, june 2014. ISSN 21502668. Available at: <https://ojs.abo.fi/ojs/index.php/jefc/article/view/524>. Date accessed: 28 oct. 2021.
Section
Original Research Articles

Keywords

drug-excipient interactions; basic drugs; oleic acid; supersaturation; precipitation kinetics; solid lipid-based systems