Mechanistic evaluation of sulfobutylether-β-cyclodextrin complexation as a formulation strategy to enhance solubility and oral exposure of BCS Class II compounds

Abstract

Poor aqueous solubility is a major cause of solubility-limited absorption and misleading pharmacokinetic outcomes during early oral drug discovery. In this study, a mechanistically guided workflow was applied in which physiologically based absorption modeling using GastroPlus®, followed by refined development classification system (rDCS) classification and solubility-limited absorbable dose (SLAD) analysis, was used to identify solubility-driven developability risks and guide formulation selection for three structurally diverse BCS Class II NCEs.

Highlights

rDCS–SLAD workflow identifies solubility-limited NCEs.
Spray-dried SBE-β-CD increases solubility by ∼ 103-fold.
Inclusion complexes show rapid dissolution and amorphization.
SBE-β-CD formulations increase exposure (AUC) 5–7-fold.
Scalable cyclodextrin platform for early formulation development.

Based on this assessment, sulfobutylether–β–cyclodextrin (SBE–β–CD) inclusion complexes were prepared by spray drying and characterized using Fourier–transform infrared spectroscopy, powder X–ray diffraction, nuclear magnetic resonance spectroscopy, and molecular docking. These orthogonal analyses confirmed non–covalent host–guest complexation, amorphization, and partial inclusion of hydrophobic aromatic regions within the cyclodextrin cavity. Complexation produced approximately three–orders–of–magnitude enhancement in apparent aqueous solubility (from ∼ 0.02–0.03 mg/mL to ∼ 24–27 mg/mL), depending on the compound and cyclodextrin ratio.

These improvements translated into clear formulation-dependent increases in vivo performance in mice, with SBE–β–CD formulations showing higher maximum plasma concentrations (Cmax) and systemic exposure (AUC) across all three compounds relative to their respective comparator formulations. Overall, this study demonstrates that integrating developability assessment tools with cyclodextrin–based formulation strategies provides a rational and scalable approach to mitigate solubility–limited absorption and improve translational decision–making for poorly soluble drug candidates.

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Materials

Three poorly soluble, hydrophobic new chemical entities (NCEs) compound 1, 2 and 3 were synthesized in-house at Sun Pharma Advanced Research Company Ltd. (SPARC). Sulfobutylether-β-cyclodextrin sodium salt (SBE-β-CD; Captisol®) was purchased from CyDex Pharmaceuticals.

Abhishek Kumar Jain, Yashoraj R. Zala, Ratnesh Jain, Mechanistic evaluation of sulfobutylether-β-cyclodextrin complexation as a formulation strategy to enhance solubility and oral exposure of BCS Class II compounds,
International Journal of Pharmaceutics, 2026, 127352, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2026.127352.