Assessing potential of precipitation inhibitors to prevent precipitation during dispersion and digestion of lipid-based formulations using in-line analytics.

Abstract

A key risk to bio-enabling performance is that transient supersaturation is not maintained for a sufficient period during intestinal transit to ensure drug absorption. The incorporation of polymeric precipitation inhibitors offer promise to mitigate the risk precipitation. Lipid-based formulations (LBFs) are a bio-enabling formulation approach where there is a risk of drug precipitation upon dispersion in intestinal fluids and/or digestion of the formulation. This study evaluated the potential of a range of precipitation inhibitors (HPMC E5, HPMC AS LG, HPMC AS MG, PVP 30, PVP VA64, Poloxamer 188, Poloxamer 407, and Soluplus®) to maintain supersaturation of celecoxib and fenofibrate loaded Type IIIA and Type IV LBFs. In addition, the impact of incorporating the precipitation inhibitor within the LBF versus concomitant addition to the biorelevant media was also explored. Real-time precipitation upon dispersion and digestion of the formulations was measured using in-situ UV fibre optic probes. The addition of a precipitation inhibitor showed promising effects for maintaining supersaturation after dispersion of the Type IV LBF in biorelevant media at low drug loading i.e. 40% drug loading. However, at a higher drug loading of 80%, no inhibition of precipitation was evident. Certain precipitation inhibitors were effective only when pre-dissolved in FaSSIF, whereas others showed effectiveness only when incorporated directly within the LBF. For Type IIIa LBFs which undergo digestion, precipitation inhibitors were generally not effective at maintaining supersaturation using a dispersion-digestion setup. Results from standard solvent shift screening were useful for predicting the effectiveness of precipitation inhibitors in Type IV LBFs, but not in Type IIIa LBFs. Observations using in-line analytics suggest that in the majority of cases precipitation inhibitor offered limited capacity to improve the apparent drug concentration during dispersion and digestion of LBFs.