Effect of Alkyl Chain Length on Physicochemical and Pharmacokinetic Performance of Aripiprazole Fatty Acid Prodrugs for Long-Acting Injectable Suspensions.

Background/Objectives: Long-acting injectable aqueous suspensions based on fatty acid prodrugs offer a compelling strategy for chronic disease management. However, the selection of optimal alkyl chain length remains largely empirical, as its influence on prodrug performance is highly system-dependent and lacks predictive guidelines. Methods: Three aripiprazole prodrugs with different alkyl chain lengths were synthesized and characterized using 1H-NMR spectroscopy and single-crystal X-ray diffraction. A series of physicochemical assessments was performed, including melting point, solubility, lipophilicity, solid-state stability, and plasma stability. The prodrugs were subsequently formulated as aqueous suspensions, which were evaluated for particle size, morphology, release behavior, cytotoxicity, and cellular uptake. Finally, intramuscular administration in rats was carried out to investigate pharmacokinetic profiles and local tolerability. Results: Physicochemical characterization revealed that chain elongation progressively reduced the melting point, solubility, wettability, and solid-state stability of these prodrugs, whereas their flexibility, lipophilicity, and plasma stability correspondingly increased. After wet milling and intramuscular administration in rats, all suspensions sustained drug release for up to one month with good tolerability. Notably, the aripiprazole lauroxil formulation exhibited superior bioavailability and a shortened subtherapeutic interval, enabling the rapid attainment of therapeutic concentrations while effectively mitigating a prolonged pharmacokinetic tail. Conclusions: These findings reinforce the favorable profile of aripiprazole lauroxil as a lead candidate and demonstrate that isostructural packing facilitates the reliable prediction of chain length-property correlations across diverse fatty acid-prodrug systems, thus providing a valuable reference for rational alkyl chain selection in the design of fatty acid-based LAI suspensions.