Combined Experimental and Computational Approaches for Ternary Solid Dispersions to Enhance the Oral Bioavailability of Penfluridol

Background: Penfluridol is a long-acting oral antipsychotic used for the treatment of schizophrenia. Although the prolonged half-life of penfluridol allows once-weekly dosing, improving patient compliance, its therapeutic potential is limited by low aqueous solubility and poor oral absorption. This study aimed to enhance the dissolution and oral bioavailability of penfluridol using solid dispersion technology. Methods: Ternary solid dispersions of penfluridol were prepared using a solvent evaporation method with various hydrophilic carriers. Following prescreening of polymeric carriers, the formulation composition was optimized using a random forest regression model. Structural characteristics and drug release behavior of the optimized formulation (PF-SD5) were evaluated through in vitro studies. Pharmacokinetic studies in rats were conducted to assess the effectiveness of PF-SD5 in enhancing oral bioavailability. Results: The optimized PF-SD5 formulation, comprising penfluridol, poloxamer 407, and polyvinylpyrrolidone K30 in a 1:3:1 ratio, exhibited a 117-fold increase in aqueous solubility compared with the pure drug. PF-SD5 achieved nearly complete drug release within 1 h across a pH range from acidic to neutral. Spectroscopic, microscopical, and thermal analyses confirmed that penfluridol transformed into an amorphous form and established molecular interactions within the carrier matrix. Pharmacokinetic studies in rats revealed approximately a 1.9-fold increase in oral bioavailability. Conclusions: Combining solid dispersion technology with machine learning-guided optimization provides an effective strategy for enhancing the oral absorption of poorly soluble penfluridol.