An Artificial Gut/Absorption Simulator: Understanding the Impact of Absorption on In Vitro Dissolution, Speciation,...

Upon dissolution, amorphous solid dispersions (ASDs) of poorly water-soluble compounds can generate supersaturated solutions consisting of bound and free drug species that are in dynamic equilibrium with each other. Only free drug is available for absorption. Drug species bound to bile micelles, polymer excipients, and amorphous and crystalline precipitate can reduce the drug solute's activity to permeate, but they can also serve as reservoirs to replenish free drug in solution lost to absorption. However, with multiple processes of dissolution, absorption, and speciation occurring simultaneously, it may become challenging to understand which processes lead to an increase or decrease in drug solution concentration. Closed, nonsink dissolution testing methods used routinely, in the absence of drug removal, allow only for static equilibrium to exist and obscure the impact of each drug species on absorption. An artificial gut simulator (AGS) introduced recently consists of a hollow fiber-based absorption module and allows mass transfer of the drug from the dissolution media at a physiological rate after tuning the operating parameters. In the present work, ASDs of varying drug loadings were prepared with a BCS-II model compound, ketoconazole (KTZ), and hypromellose acetate succinate (HPMCAS) polymer. Simultaneous dissolution and absorption testing of the ASDs was conducted with the AGS, and simple analytical techniques were utilized to elucidate the impact of bound drug species on absorption. In all cases, a lower amount of crystalline precipitate was formed in the presence of absorption relative to the nonsink dissolution "control". However, formation of HPMCAS-bound drug species and crystalline precipitate significantly reduced KTZ absorption. Moreover, at high drug loading, inclusion of an absorption module was shown to enhance ASD dissolution. The rank ordering of the ASDs with respect to dissolution was significantly different when nonsink dissolution versus AGS was used, and this discrepancy could be mechanistically elucidated by understanding drug dissolution and speciation in the presence of absorption.