Lipid-based formulations are commonly evaluated as systems that improve the apparent solubility of poorly water-soluble drugs, yet their performance is generated within a gastrointestinal environment that changes continuously after administration. Digestion, bile salt and phospholipid availability, meal composition, luminal pH, gastric emptying, intestinal transit, drug precipitation, absorptive removal, and epithelial lipid processing can alter both the formulation and the physiological environment against which it is tested. Consequently, the concentration of drug recovered in an aqueous or colloidal phase is not necessarily equivalent to the concentration thermodynamically available for membrane transport, and precipitation observed during digestion is not necessarily equivalent to loss of absorption. This critical review examines lipid formulation classes as dynamic states rather than static vehicles and evaluates how digestive transformation, colloidal restructuring, physiological variability, supersaturation, and absorptive processes change the interpretation of formulation performance. Particular attention is given to bile salt and phospholipid variability, fed–fasted transitions, pH and transit, and the time relationship between precipitation and absorption. The review develops a proposed physiology-conditioned formulation-state interpretation in which formulation performance is judged across sequential luminal and absorptive states, with explicit validation boundaries between solubilization, free drug, permeability, and systemic exposure. This interpretation does not replace established formulation classifications or claim prospective prediction. Instead, it identifies where apparently favorable in vitro behavior may fail to transfer because the physiological condition, measurement compartment, time scale, or absorptive sink has changed.
IJPRAS
