Comparative partitioning of model drugs across five pharmaceutical oils: Implications for passive loading in emulsions and oleosomes

In biphasic delivery systems, particularly macro-emulsions and oleosomes, sufficient passive incorporation of drugs into the oil phase is a critical formulation attribute. Higher oil-phase loading not only ensures efficient drug encapsulation but also enables the development of robust, scalable, and clinically relevant lipid-based delivery platforms. Passive loading is governed by the interplay between drug properties and formulation physicochemical characteristics. From a molecular perspective, the ionization state of a drug at different pH values strongly influences oil–water partitioning, as unionized species can more effectively partition into the hydrophobic oil phase. At the same time, pharmaceutical oils differ in polarity, chain length, and glyceride backbone, making systematic evaluation of oil-dependent partitioning essential for rational formulation design. This study investigated the distribution behavior of three model compounds with distinct ionization characteristics, including melatonin (neutral), indomethacin (weak acid), and amitriptyline hydrochloride (weak base). Their partitioning was evaluated across five representative oil phases, including Labrafac PG (propylene glycol dicaprylocaprate), Labrafac Lipophile WL 1349 (medium-chain triglycerides), Peceol (glyceryl monooleate), Maisine CC (glyceryl monolinoleate), and canola oil (long-chain triglycerides), over the pH range of 3–10. All compounds exhibited pH-dependent partitioning consistent with their ionization profiles; however, notable differences emerged among oils. Melatonin displayed pronounced oil-dependent shifts, transitioning between hydrophilic and oleophilic behavior depending on the oil phase. A key finding was that partitioning trends, particularly for indomethacin and amitriptyline, were governed primarily by microstate transitions rather than octanol–water log D values, with ionization capable of reversing apparent hydrophilic and oleophilic tendencies. This mechanistic distinction underscores the importance of experimentally measured oil–water log D values, interpreted alongside microstate behavior, especially for compounds with multiple pKa values where charge-state distributions change rapidly with pH. From an oil perspective, short-chain glycerides (di- or triglycerides) exhibited comparable partitioning, whereas long-chain systems revealed clear differences between di- and triglyceride backbones. Among the three drugs, indomethacin displayed the greatest sensitivity to oil structure. These findings demonstrate that both drug ionization and oil composition determine passive loading efficiency in biphasic systems. Systematic partition profiling across multiple oils provides a rational, cost-effective approach to predict drug–oil compatibility and to support preformulation excipient selection in emulsions and oleosome-based lipid delivery systems.