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

Abstract

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.