Comparative Dissolution Enhancement Strategies for BCS Class II Drugs: A Rivaroxaban- Mechanistic and Translational Review

“Originally published in IJPPR Human Journals”.

ABSTRACT Poor aqueous solubility remains a primary constraint in the oral development of Biopharmaceutics Classification System (BCS) Class II drugs, where dissolution rather than permeability governs systemic exposure. Although numerous formulation strategies have been proposed to overcome dissolution-limited absorption, comparative mechanistic evaluation and translational assessment remain insufficiently integrated in the literature. This review critically examines major dissolution enhancement platforms— including nanocrystal technology, amorphous solid dispersions, lipid-based self-emulsifying systems, liquisolid compacts, cyclodextrin complexation, and auxiliary excipient-based approaches—from the perspective of mechanistic action, supersaturation behaviour, precipitation control, and pharmacokinetic translation. Rivaroxaban, a direct Factor Xa inhibitor characterized by low aqueous solubility and dissolution-sensitive bioavailability, is employed as a representative model compound to contextualize platform performance. Comparative analysis demonstrates that while surface area reduction accelerates dissolution kinetics, amorphization and lipid-mediated solubilization provide greater thermodynamic driving force for absorption but introduce stability and precipitation challenges. Sustained supersaturation and precipitation inhibition emerge as central determinants of in vivo relevance, underscoring the limitation of dissolution magnitude as a standalone metric. Furthermore, the review evaluates the role of biorelevant dissolution testing and physiologically based pharmacokinetic (PBPK) modelling in strengthening in vitro–in vivo correlation (IVIVC) for solubility-limited compounds. Evidence suggests that predictive formulation development requires integration of dissolution kinetics, supersaturation stability, gastrointestinal physiology, and dose number considerations rather than empirical platform selection. By synthesizing mechanistic insights with rivaroxaban-specific formulation evidence, this review proposes a strategy selection framework aimed at improving translational reliability of dissolution enhancement approaches. Emphasis on precipitation control, stability profiling, and biorelevant evaluation is essential to advance rational oral delivery design for BCS Class II drugs. Keywords: BCS Class II, dissolution enhancement, rivaroxaban, solid dispersion, SEDDS, nanocrystals, IVIVC, bioavailability