Drug precipitation-permeation interplay: supersaturation in an absorptive environment

The present study investigated the interplay between supersaturation, absorption, precipitation, and excipient-mediated precipitation inhibition by comparing classic precipitation assessment in a non-absorption environment with precipitation/permeation assessment in an absorption environment. Loviride and HPMC-E5 were selected as poorly soluble model drug and precipitation inhibitor, respectively.

To investigate supersaturation in an absorptive environment, supersaturation was induced at different degrees (DS), using a solvent shift method, in shaken Caco-2 Transwell® inserts containing fasted state simulated intestinal fluid (FaSSIF); to simulate a non-absorption environment, the inserts were parafilm-sealed and did not contain a cell monolayer. Donor and acceptor compartments were sampled as a function of time to determine precipitation kinetics and transport, respectively.

In absence of precipitation, loviride transport increased proportionally with the initial DS; however, precipitation limited the supersaturation-induced transport enhancement. Loviride precipitation was found to be less extensive in an absorption environment compared to a non-absorption environment. As a result, the optimal DS obtained in a non-absorption environment (highest amount maintained in solution) did not correlate with the highest transport in an absorption environment. In addition, the impact of HPMC-E5 on loviride transport was inferior to its precipitation inhibitory capacity observed in a non-absorption environment.

For the first time, the present study explicitly demonstrated that implementation of permeation in precipitation assays is critical to predict the impact of supersaturation, precipitation, and precipitation inhibition on the absorption of poorly soluble drugs.