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

• Main Authors: Zdravka Misic, Dubravka Šišak Jung, Georg Sydow, Martin Kuentz
• Format: Article
• Language: English
• Published: International Pharmaceutical Excipients Council
• Series: Journal of Excipients and Food Chemicals
• Online Access: http://jefc.scholasticahq.com/article/950-understanding-the-interactions-of-oleic-acid-with-basic-drugs-in-solid-lipids-on-different-biopharmaceutical-levels.pdf

There has recently been increasing interest in understanding the impact of intestinal supersaturation on the absorption of poorly water-soluble drugs. Focus has been mostly on the effect of excipients on maintaining drug supersaturation. The aim of the this study was to explore the effects of drug-excipient interactions of an anhydrous formulation, when dispersed in simple buffer media and, in particular, focusing on precipitation kinetics. A solid lipid-based formulation comprising of PEG-32 stearate and an oleic acid (OA) (8:2 w/w) was developed using loratadine (pKa = 5.3) and carvedilol (pKa = 7.8) as the model drugs. UV/FTIR spectroscopy and viscometry were used to characterize the drug-OA molecular interactions in solution and the solid formulations were studied using x-ray diffraction, thermal analysis and van’t Hoff solubilitytemperature plots. Precipitation kinetics of the drug formulations was monitored in real-time in a phosphate buffer (pH = 6.5) using focused beam reflectance measurements. The addition of OA in the formulations resulted in a substantial increase in drug solubility. Although the drug-OA interactions appeared to be partially lost upon dispersion of the formulation, the extent of precipitation markedly decreased 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 (GI) tract to the induction time (the onset of crystalline precipitation). Without OA, Pnc was already taking critical values (>1), while the anhydrous formulation was still below saturation for both drugs. The addition of OA resulted in amorphous rather than crystalline precipitates, which could be advantageous for drug re-dissolution and absorption. 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.