Purpose: Since the majority of newly developed NCEs are weak bases, simulation of gastrointestinal drug dissolution and precipitation is key for the prediction of oral absorption in humans, in particular when precipitation of the drug in the gastrointestinal tract is likely to occur.
Due to the limited amount of API available and tight timelines in early phases of drug discovery, a time-efficient and economical precipitation inhibitor screening has been developed to study the potential of solubility-enhancing excipients to prevent a drug from precipitation during GI transit. Suitable precipitation inhibitors were identified, applying a previously developed automated small-scale in vitro transfer model. In vivo rat PK studies were performed to address the question whether the in vitro findings can be translated to in vivo.
Methods: The in vitro transfer model represents a two-compartmental dissolution model, simulating the transfer of API from the donor (stomach) into the acceptor (small intestine) compartment. 20 mg ketoconazole (one tenth of the human dose of 200 mg) were dissolved in SGF, pH 2.0 and subsequently transferred into FaSSIF, pH 6.5 using an automated small-scale in vitro transfer model. 0.1% HPMAS-LF, 0.1% Soluplus®, and 0.25% Tween20 were added to the simulated gastric compartment to investigate the effect of precipitation inhibitors on the supersaturation and precipitation behavior of ketoconazole. In vivo rat PK studies were performed as follows: 26 mg/kg of ketoconazole in an oral suspension, containing ketoconazole, 0.25% HPMC in water, and the respective excipient, were administered to Wistar rats. The respective blood samples were analyzed by HPLC.
Results: Adding HPMCAS-LF, Soluplus®, and Tween20 to the simulated gastric compartment yielded both an increased supersaturation and a decreased precipitation rate of ketoconazole upon entering the simulated intestinal compartment. HPMCAS-LF was observed to be the most effective precipitation inhibitor, followed by Soluplus® and Tween20. Cmax increased 1.4-fold using the three excipients compared to the neat API. Additionally, the AUC0-120 min increased 2.8-fold, 2.4-fold, and 1.6-fold using HPMCAS-LF, Soluplus®, and Tween20.
However, the suitable in vitro precipitation inhibitors yielded in a decreased Cmax and AUC0-24 h and an increased tmax value in in vivo rat PK studies. AUC decreased 1.7-fold, 1.5-fold, and 1.2-fold using HPMCAS-LF, Soluplus®, and Tween20 compared to the neat API. Consequently, in vivo findings were observed to be completely reverse under all conditions, compared to the in vitro data.
Conclusion: Using the in vitro transfer model and the newly developed precipitation inhibitor screening, a correlation between in vitro and in vivo results could not be obtained. Decreased in vivo Cmax and AUC and increased tmax values caused by the addition of in vitro precipitation inhibitors may indicate strong interactions between API and excipients, both in vitro and in vivo, which may, in turn, lead to a reduced absorption in vivo. Compared to the in vivo situation, the lack of drug absorption from the acceptor compartment in the in vitro transfer model may also lead to an overprediction of precipitation of ketoconazole.