Synergistic role of monoacyl phospholipids and precipitation inhibitor in ternary solid dispersions: a case study of Aripiprazole.

The use of phospholipids in solid dispersions represents a promising strategy for overcoming the solubility barriers of BCS Class II compounds; however, the impact of monoacyl phospholipids (MAPC) on supersaturation maintenance requires systematic optimization. This study investigated the biopharmaceutical performance of MAPC-based binary and ternary solid dispersions, using aripiprazole as a low-solubility model drug. Binary dispersions prepared by solvent evaporation induced only partial amorphization, the integration of a precipitation inhibitor (hydroxypropyl methylcellulose phthalate, HPMCP-L55) in ternary systems proved critical, yielding fully amorphous formulations with physical stability exceeding 90 days. In vitro characterization demonstrated that the ternary dispersion enabled an ~ 85-fold increase in apparent solubility and a superior dissolution profile compared to the crystalline drug and binary dispersions. Importantly, this increase in apparent solubility was accompanied by a significant but non-proportional increase in steady-state flux (~ 4-fold) across the Permeapad® barrier, highlighting the distinction between apparent solubility enhancement and the molecularly dissolved drug fraction that governs membrane transport. Pharmacokinetic evaluation in rats further validated the platform, revealing a 6.3-fold improvement in oral bioavailability (AUC) along with rapid absorption onset. Overall, the combination of MAPC and polymeric precipitation inhibitors provides a robust strategy for stabilizing amorphous drugs, while the integrated dissolution–permeation behavior offers a mechanistically relevant predictor of in vivo performance, as supported by an exploratory IVIVC (R² = 0.9527).