Background: The solubilization of poorly water-soluble drugs remains challenging. The
purpose of this study was to design a liquid formulation that can improve the solubility of poorly
water-soluble and weakly acidic ST-246, an anti-smallpox drug.
Methods: Soluble ternary cyclodextrin complexations (t-CDs) containing ST-246, 2-hydroxypropyl-β-
cyclodextrin (HP-β-CD) and meglumine (MEG) were prepared and optimized. The optimized t-CDs
were further characterized using a scanning electron microscope (SEM), Powder X-ray Diffractometry
(PXRD), Differential Scanning Calorimetry (DSC), Fourier Transform Infrared Spectroscopy
(FTIR) and Nuclear Magnetic Resonance Spectroscopy (NMR).
Results: The solubility of ST-246 improved dramatically from 3 µg/ml (in water, 37°C) to 50 mg/ml
in the optimized t-CDs (ST-246/MEG/HP-β-CD, 1:2:6 weight ratio). The results suggested that the
drug was associated with MEG through hydrogen bonds and then included into the hydrophobic cavity
of HP-β-CD, which might be a major factor for solubility improvement. To determine the exact
inclusion mechanism, a Phase Soluble Study (PSS) was also conducted, and it indicated that a 1:1
soluble complex was formed between ST-246 and HP-β-CD and that the action mechanism of MEG
was complicated and relied on more than pH modulation.
Conclusion: Generally, the optimized ternary cyclodextrin complexation might be a potential
formulation strategy for enhancing the solubility and bioavailability of poorly water-soluble ST-246.