In vitro tools for evaluating novel dosage forms of poorly soluble, weakly basic drugs: case example ketoconazole

Area of Science:

• Pharmaceutical Sciences
• Drug Delivery Systems
• In Vitro Testing

Background:

• Poorly soluble compounds present formulation challenges for oral administration.
• Ketoconazole (KETO), a model compound, requires enhanced delivery strategies.
• Hydroxypropyl-β-cyclodextrin (HP-β-CD) and Soluplus® are excipients used to improve drug solubility.

Purpose of the Study:

• To compare in vitro tools for evaluating novel ketoconazole formulations.
• To assess the influence of formulations on solubility, dissolution, and transfer behavior.
• To forecast the oral administration performance of binary and ternary KETO formulations.

Main Methods:

• Evaluation of solubility, dissolution tests, and a miniaturized transfer model.
• Comparison of pure ketoconazole (KETO) with binary (HP-β-CD) and ternary (HP-β-CD/Soluplus®) formulations.
• Testing in simulated gastric and intestinal media, including pH 6.5 FaSSIF.

Main Results:

• Both binary and ternary formulations significantly enhanced KETO solubility (p < 0.05).
• Dissolution was nearly complete in simulated fasted stomach and fed small intestine media.
• In pH 6.5 FaSSIF, KETO release was significantly higher for formulations (32%/95%) versus pure drug (<10%).
• The ternary complex demonstrated superior supersaturation stabilization and precipitation inhibition.
• The miniaturized transfer model effectively ranked formulation performance.

Conclusions:

• Formulations with HP-β-CD and Soluplus® significantly improve ketoconazole solubility and release.
• A miniaturized transfer model is a valuable tool for rank-ordering drug formulations.
• In vitro models are crucial for predicting in vivo performance of poorly soluble drugs.